Review

Sigma1 (s1) receptor antagonists represent a new strategy

against cocaine addiction and toxicity

Tangui Mauricea,*, Remi Martin-Fardonb, Pascal Romieua, Rae R. Matsumotoc

aCNRS UMR 5102, University of Montpellier II, c.c. 090, place Eugene Bataillon, 34095 Montpellier cedex 5, FrancebDepartment of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92307, USA

cDepartment of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center,

College of Pharmacy, P.O. Box 26901, Oklahoma City, OK 73190, USA

Abstract

Cocaine is a highly addictive substance abused worldwide. Its mechanism of action involves initially inhibition of neuronal monoamine

transporters in precise brain structures and primarily the dopamine reuptake system located on mesolimbic neurons. Cocaine rapidly

increases the dopaminergic neurotransmission and triggers adaptive changes in numerous neuronal circuits underlying reinforcement,

reward, sensitization and the high addictive potential of cocaine. Current therapeutic strategies focus on counteracting the cocaine effects

directly on the dopamine transporter, through post-synaptic D1, D2 or D3 receptors or through the glutamatergic, serotoninergic, opioid or

corticotropin-releasing hormone systems. However, cocaine administration also results in the activation of numerous particular targets.

Among them, the sigma1 (s1) receptor is involved in several acute or chronic effects of cocaine. The present review will first bring concise

overviews of the present strategies followed to alleviate cocaine addiction and animal models developed to analyze the pharmacology of

cocaine addiction. Evidence involving activation of the s1 receptor in the different aspects of cocaine abuse, will then be detailed, following

acute, repeated, or overdose administration. The therapeutic potentials and neuropharmacological perspectives opened by the use of selective

s1 receptor antagonists in cocaine addiction will finally be discussed. q 2002 Elsevier Science Ltd. All rights reserved.

Keywords: Cocaine addiction; Dopaminergic systems; s1 receptor; s1 antagonists; Sensitization; Conditioned place preference; Convulsion; Lethality

Contents

1. The s1 receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500

1.1. Identification of the s1 receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500

1.2. Anatomical localization of the s1 receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501

1.2.1. Central distribution of the s1 receptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501

1.2.2. Peripheral organs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501

1.3. The s1 receptor as an intracellular calcium mobilization modulatory protein . . . . . . . . . . . . . . . . . . . . . . . . . 502

0149-7634/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.

PII: S0 14 9 -7 63 4 (0 2) 00 0 17 -9

Neuroscience and Biobehavioral Reviews 26 (2002) 499–527

www.elsevier.com/locate/neubiorev

* Corresponding author. Tel.: þ33-4-67-14-42-70; fax: þ33-4-67-14-42-51.

E-mail address: maurice@univ-montp2.fr (T. Maurice).

Abbreviations: (þ )-3-PPP, (þ )-3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine; 5-HT, serotonine; 5-HTT, serotonine transporter; 6-OHDA,

6-hydroxydopamine; ACTH, adrenocorticotropin hormone; BD1008, N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine; BD1047,

N-[2-(3,4-dichlorophenyl)ethyl]-N,N0,N0-trimethylethylenediamine; BD1063, 1-[2-(3,4-dichloro-phenyl)ethyl]-4-methylpiperazine; BD737, 1S,2R-(2)-cis-

N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)cyclohexyl-amine; BMY-14,802, a-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine

butanol; BTCP, 1-(2-benzo(b )thiophenyl)cyclohexyl]piperidine; cAMP, adenosine 30-50-monophosphate; CPP, 3-(2-carboxypiperazine-4-yl)propyl-1-

phosphonic acid; CSP, conditioned spatial preference; CREB, cAMP response element-binding protein; CRH, corticotropin-releasing hormone; DA,

dopamine; DAT, dopamine transporter; DOPAC, 3,4-dihydroxyphenylacetic acid; DTG, 1,3-di-O-tolylguanidine; DuP 734, 1-(cyclopropylmethyl)-4-(20-(400-

fluorophenyl)-20-oxoethyl)piperidine hydrobromide; E-5842, 4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-[4-(1,2,4-triazol-1-yl)butyl]piperidine citrate; EMD

57445, (S )-(2)-[4-hydroxy-4-(3,4-benzodioxol-5-yl)-piperidin-1-ylmethyl]-3-(4-methoxyphenyl) oxazolidin-2-one, panamesine; FRA, Fos-related antigens;

GBR 12909, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine; HPA, hypothalamic-pituitary-adrenocortical axis; HVA, homovanillic

acid; InsP3, inositol trisphosphate; MAPK, mitogen-associated protein kinase; NE-100, N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine

monohydrochloride; NMDA, N-methyl-D-aspartate; NPA, R(2)-propylnorapomorphine hydrochloride; NPC 16377, 6-[6-(4-hydroxypiperidinyl) hexyloxy]-

3-methylflavone; PCP, phencyclidine; PKA, cAMP-dependent protein kinase A; PRE-084, 2-(4-morpholino)ethyl1-phenylcyclohexane-1-carboxylate

hydrochloride; S-21377, 2-[4-(4-methoxy-benzyl)piperazin-1-yl-methyl]4-oxo[4H ]-benzo-thiazolin-2-one; S-21378, 2[(4-benzyl-piperazin-1-

yl)methyl]naphthalene dichlorydrate; SR 31742A, cis-3-(hexahydro azepin-1-yl)1-(3-chloro-4-cyclohexylphenyl)propene-1; U-50,488H, trans-3,4-

dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzene acetamide methane sulfonate hydrate; XJ448, 1-(cyclopropylmethyl)-4-(20,400-cyanophenyl)-

20-oxoethyl)-piperidine hydrobromide.

1.4. Modulation of dopaminergic systems by s1 receptor ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503

2. Cocaine addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504

2.1. Current investigations for pharmacotherapy to cocaine addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504

2.1.1. Strategies targeting DA receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505

2.1.2. Strategies using DA reuptake inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505

2.1.3. Strategies focusing on 5-HT systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506

2.1.4. Strategies using opioids compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506

2.1.5. Strategies using glutamate receptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506

2.1.6. Strategies using CRH antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507

2.2. Animal models of behavior for reward and reinforcement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507

2.2.1. Neuroadaptive changes associated with repeated drug administration—sensitization . . . . . . . . . . . . . . 507

2.2.2. Neuroadaptive changes associated with repeated drug administration—conditioning . . . . . . . . . . . . . . 507

2.2.3. Drug discrimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508

2.2.4. Self-administration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508

2.2.5. Relapse models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509

3. Involvement of the s1 receptor in cocaine effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509

3.1. Cocaine binding to the s1 receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509

3.2. Involvement of the s1 receptor in the acute stimulant effects of cocaine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 510

3.3. Involvement of the s1 receptor in the sensitization induced by cocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 510

3.4. Involvement of the s1 receptor in the cocaine-induced rewarding properties measured using a CSP paradigm . 510

3.5. By which mechanism could s1 receptor antagonists block cocaine’s effects? . . . . . . . . . . . . . . . . . . . . . . . . . 511

4. Cocaine overdose. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515

4.1. Involvement of the s1 receptor in cocaine-induced convulsions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515

4.2. Involvement of the s1 receptor in cocaine-induced lethality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517

4.3. s1 receptors and mechanisms of cocaine-induced behavioral toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519

5. Perspectives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520

1. The s1 receptor

1.1. Identification of the s1 receptor

It is now well established that s receptors represent a

unique binding site in brain and peripheral organs, distinct

from any other known proteins. However, when they were

initially proposed by Martin and colleagues [152] to account

for the psychotomimetic effects of N-allylnormetazocine

((^ )-SKF-10,047) in the morphine-dependent chronic

spinal dog, they were initially classifed as ‘opiate/s’ sites.

It was rapidly evident that most of the behaviors elicited by

the drug were resistant to blockade by classical opiate

receptor antagonists naloxone or naltrexone [292]. The s

receptors were thus distinguished from other classical m-,

k-, and d-opiate receptors [220]. The s receptors were then

confounded with the high affinity phencyclidine (PCP)

binding sites, located within the ion channel associated with

the NMDA-type of glutamate receptor, because of similar

affinities of these sites for several compounds, including

PCP and (þ )-SKF-10,047 [220]. The confusion was cleared

up by the availability of more selective drugs, including

dizocilpine or thienylcyclidine for the PCP site; 1,3-di-O-

tolylguanidine (DTG), (þ )-pentazocine, (þ )-3-(3-hydro-

xyphenyl)-N-(1-propyl)-piperidine ((þ )-3-PPP), igmesine

(JO-1784), (þ )-cis-N-methyl-N-[2-(3,4-dichlorophenyl)

ethyl]-2-(1-pyrrolidinyl)cyclohexylamine (BD737), among

others, for the s site. The pharmacological identification of

s sites was characterized by their ability to bind several

chemically unrelated drugs with high affinity, including

psychotomimetic benzomorphans, PCP and derivatives,

cocaine and derivatives, amphetamine, certain neuroleptics,

many new ‘atypical’ antipsychotic agents, anticonvulsants,

cytochrome P450 inhibitors, monoamine oxidase inhibitors,

histaminergic receptor ligands, peptides from the neuro-

peptide Y (NPY) and calcitonin gene-related peptide

(CGRP) families, and several steroids [162,165,166,298].

The pharmacological identification and localization of s

binding sites was achieved using various radioligands,

including [3H](þ )-SKF-10,047, [3H](þ )-3-PPP, [3H]halo-

peridol, [3H]DTG, [3H](þ )-pentazocine [49,87,140,172,

277]. Biochemical studies allowed the distinction of two

classes of s sites, termed s1 and s2 [219]. The two sites can

be distinguished based on their different drug selectivity

patterns and molecular weights. The s1 site is a 25–30 kDa

single polypeptide, and the s2 site is an 18–21 kDa protein

that has not yet been cloned [22,93,94,219]. The s1 site

presents a high affinity and stereoselectivity for the (þ )-

isomers of SKF-10,047, pentazocine and cyclazocine,

whereas s2 sites have lower affinity and show the reverse

stereoselectivity [94]. DTG, (þ )-3-PPP and haloperidol are

non-discriminating ligands with high affinity on both

subtypes. In addition, s1 sites are allosterically modulated

by phenytoin [190] and sensitive to pertussis toxin and to the

modulatory effects of guanosine triphosphate [104,105,

183]. It also has been shown that several drugs, such as

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527500

haloperidol, reduced haloperidol, a-(4-fluorophenyl)-4-(5-

fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY-14,802),

rimcazole, or N,N-dipropyl-2-(4-methoxy-3-(2-phenyl-

ethoxy)phenyl) ethylamine (NE-100) act as antagonists in

several physiological and behavioral tests relevant to the s1

pharmacology [125,155,200,279,280]. However, most of

them are non-selective and also bind to other pharmaco-

logical targets.

The s1 receptor cDNA has been cloned from guinea-pig

liver [90], human placental cell line, T leukemia Ichikawa

cell line and human brain [107,119,217], mouse kidney and

brain [201,253], and rat brain [173,252]. The amino acid

sequences of the purified proteins are highly similar, with a

87–92% identity and 90–93% homology between species.

The protein sequence also shared a similarity, 33% identity

and 66% homology, with a fungal sterol C8–C7 isomerase

[90]. However, it shares no homology to the related

mammalian enzyme or any other mammalian protein,

indicating that the s1 receptor is a distinct entity from any

other known receptors and that an identical s1 receptor is

expressed in peripheral tissues and brain. The promoter

region sequence of the s1 receptor contains consensus

sequences for the liver-specific transcription factors nuclear

factor (NF)-1/L, activator protein (AP)-1, AP-2, IL-6RE,

NF-GMa, NF-GMb, NF-kB, steroid response element,

GATA-1, Zeste, for the xenobiotic responsive factor called

the arylhydrocarbon receptor, and for a putative signal for

retention in the endoplasmic reticulum [217], suggesting

that the receptor transcription could be related by immediate

early genes.

1.2. Anatomical localization of the s1 receptor

1.2.1. Central distribution of the s1 receptor

The anatomical distribution of the s1 receptor is now

well characterized. It has been initially described in the

rodent brain using autoradiographic studies, using various

radiotracers [49,81,87,106,140,172,198,273,298] and, more

recently, using in situ hybridization [124,321] or immuno-

histochemical techniques [5,207]. The s1 receptor is

particularly concentrated in specific areas throughout limbic

systems and brainstem motor structures. The highest levels

of s1 immunostaining can be observed in the granular layer

of different structures, including olfactory bulb, hypothala-

mic nuclei, hippocampus and pyramidal layers of the

hippocampus [5,207]. In addition, various other areas

exhibit intense to moderate s1 immunostaining, including

the superficial cortical layers, the different layers of the

olfactory bulb, the midbrain, motor nuclei of the hindbrain

and the dorsal horn of the spinal cord. Only faint

immunostaining was observed in the granular layer of the

cerebellum. The immunostaining observed in dopaminergic

structures of the C57BL/6 mouse is shown in Fig. 1. The

caudate putamen, septum, nucleus accumbens and amyg-

dala, showed a moderately concentrated but quite intense

labeling in the mouse [207].

The subcellular localization was achieved recently using

electron microscope studies [5,166,207]. The s1 receptor

was found to be mostly associated with neuronal perikarya

and dendrites, where it is either dispersed throughout the

cytoplasm or associated with membranes in the rat [5]. This

receptor appears to be more concentrated and exclusively

associated with microsomal, plasmic, nuclear or endo-

plasmic reticulum membranes in the mouse brain. In

addition, the s1 receptor is particularly concentrated within

post-synaptic thickenings, although it could also be

observed at the pre-synaptic level. The s1 receptor is

known to contain an endoplasmic reticulum sequence [90]

and recent studies demonstrated that once activated the s1

receptor is translocated from the endoplasmic reticulum to

the plasma or nuclear membrane [91,188].

1.2.2. Peripheral organs

The s1 receptor is also widely distributed in peripheral

organs, such as the digestive tract [234,235], vas deferens

[57,272], liver [93,167,240], kidney [21], heart [63], adrenal

medulla [233,315], pituitary, testis and ovaries [315,316],

and blood mononuclear cells [315].

The subcellular distribution of [3H](þ )-SKF-10,047

binding to s1 sites was extensively investigated using

biochemical techniques in the rat liver [167,240,241]. The

distribution profile of the radioligand binding coincided

with that of NADPH cytochrome c reductase, bringing the

first evidence that the s1 receptor was located on the

endoplasmic reticulum. Very low [3H](þ )-SKF-10,047

binding was associated with plasma membrane, mitochon-

drial and nuclear markers.

The digestive tract was also extensively studied [234,

235]. Receptor binding assays and autoradiographic

analyses of tissue sections from the esophagus to the

colon were incubated in the presence of s1 receptor ligands.

An intense localization was observed in the mucosal regions

and the subinucosal plexus with the highest concentrations

in the subinucosal plexus of the duodenum, but with a poor

labeling of the muscular regions. This distribution of s1

receptors suggested a functional role in ion exchange and

secretion as well as gut motility [271]. Interestingly, the s1

receptor was initially cloned from peripheral organs and cell

lines, revealing that the peripheral and central s1 receptor

are strictly identical.

The s1 receptors are also present on cardiomyocytes and

the effect of s1 agonists were extensively studied [63,64,

148,194,195]. The s1 receptors seem to play an important

role in the regulation of cardiac function by exerting a

complex effect on the amplitude and frequencies of

contraction, Ca2þ fluxes and intracellular Ca2þ concen-

tration transients [63]. In particular, exposure of cardiac

myocytes to the s1 receptor agonists DTG, (þ )-3-PPP, (þ )-

pentazocine, or BD737 potentiated the electrically evoked

amplitude of contraction and Ca2þ transients [63,64,194,

195]. In turn, blockade of the s1 receptor could allow

cardioprotection in pathological conditions, since the s1

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527 501

antagonist DuP 734 reversed the decrease in ventricular

fibrillation threshold induced by either post-infarction

cardiosclerosis or immobilization stress [148].

The presence of high densities of s1 receptors, mediating

physiological and behavioral effects at pharmacologically

relevant doses, in peripheral organs is of particular

importance in cocaine addiction. Indeed, cocaine, adminis-

tered systemically, is known to affect not only the brain, but

also the heart, lung, digestive tract, kidney, immune and

endocrine systems. Under chronic or overdose intoxication,

peripheral s1 receptors are likely to be involved in cocaine’s

effects.

1.3. The s1 receptor as an intracellular calcium

mobilization modulatory protein

The s1 receptor is involved in a direct modulation of

intracellular calcium ([Ca2þ]i) mobilizations, through a

complex mechanism. Initially, Ela and collaborators [63]

showed that exposure of cardiomyocytes in culture to s1

receptor agonists, such as (þ )-3-PPP, haloperidol, and (þ )-

pentazocine, exerted specific changes in contractility,

[Ca2þ]i transients and beating rates. The time-course of

changes in the contractility and [Ca2þ]i transients showed a

complex but reproducible pattern, with an initial decrease,

followed by an important increase, and a final decrease. The

increase in [Ca2þ]i and following decrease appeared to be

mediated by corresponding changes in Ca2þ influx [63].

These authors suggested that the time course of the s1

agonist effect involved a primary action on Ca2þ channels or

an action of Ca2þ fluxes via modulation of Kþ channels.

Later on, the same group suggested that the high affinity s1

receptor ligands BD-737 and N-[2-(3,4-dichlorophenyl)

ethyl]-N,N0,N0-trimethylethylenediamine (BD-1047)

Fig. 1. Light microscope micrographs of dopaminergic areas of the C57BL/6 mouse brain showing intense to moderate s1 receptor immunostaining: caudate

putamen (A); nucleus accumbens (B); septum (C); amygdala (D); cortex (E); ventral tegmental area (F). Note that numerous intensely immunostained neuron-

like cells are present throughout each dopaminergic structure, as indicated by arrows. Abbreviations: aca: anterior part of the anterior commissure; Gem:

gemini hypothalamic nucleus. Scale bars ¼ 100 mm. Courtesy of V.L. Phan (INSERM U. 336, Montpellier, France).

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527502

potentiated the electrically evoked amplitudes of contrac-

tion and Ca2þ transients by activation of phospholipase C

and elevation of intracellular inositol trisphosphate (InsP3)

level [195].

The role of the s1 receptor in regulating Ca2þ was,

however, extensively studied in NG-108 cells [91]. The s1

agonists (þ )-pentazocine and PRE-084 potentiated the

bradykinin-induced increase in [Ca2þ]i in a bell-shaped

manner. After endoplasmic reticulum Ca2þ depletion, the

depolarization-induced increase in [Ca2þ]i in the cells was

potentiated by PRE-084 but inhibited by (þ )-pentazocine.

Both effects were blocked by an antisense oligodeoxy-

nucleotide targeting the s1 receptor [91]. More recently, the

same authors [92] suggested that the s1 receptor could

regulate the coupling of the InsP3 receptor with the

cytoskeleton via an ankyrin B protein. They observed that

(þ )-pentazocine dissociated ankyrin B from InsP3 receptor

in NG-108 cells, and this dissociation correlated with the

efficacy of each ligand in potentiating the Ca2þ efflux

induced by bradykinin. These results, coherent with the s1

receptor subcellular localization [207], suggested that the

s1 receptor may play a particular role of sensor/modulator

for the neuronal intracellular Ca2þ mobilizations and

consecutively for extracellular Ca2þ influx. This cellular

role could explain the effective but apparently non-selective

neuromodulation mediated by the s1 receptor on several

neurotransmitter systems, including dopaminergic

pathways.

1.4. Modulation of dopaminergic systems by s1 receptor

ligands

Evidence that the s1 receptor efficiently modulates the

dopaminergic neurotransmission arose from studies exam-

ining the effect of s1 receptor ligands on DA synthesis,

metabolism, and release or the electric activity of DA

neurons. Different technical approaches and numerous s1

compounds acting more or less selectively were, however,

employed, which led to some confusion on the resulting

observations.

The effects of s1 receptor ligands on extracellular DA

concentration was determined in several brain areas using

the in vivo microdialysis technique [85,86,115,206,256].

Systemic administrations of the s1 receptor agonists DTG,

(þ )-pentazocine, (þ )-SKF-10,047, DUP 734 or (2 )-

butaclamol significantly increased the extracellular DA

concentration in the striatum [86,206]. The s1 receptor

ligands facilitated DA release from nigrostriatal and

presumably mesocorticolimbic neurons through a non-

transporter-mediated mechanism. Locally, the intrastriatal

infusion of (þ )-pentazocine or DTG through a microdialy-

sis probe resulted in a biphasic effect on extracellular DA

concentration, a brief increase followed by a prolonged

decrease [85]. Interestingly, the initial increase but not the

subsequent decrease in DA release produced by (þ )-

pentazocine was attenuated by the NMDA antagonist 3-

(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (CPP).

DA release in the striatum may thus be modulated by

multiple s1 receptor subtypes and NMDA receptors mediate

the stimulatory effect of s1 ligands on DA release in the

striatum [85]. Systemic administration of the s1 receptor

agonist (þ )-3-PPP was found to reduce DA levels in the

striatum, in a BMY-14,802-sensitive manner [115].

The s1 receptor ligands also affected the extracellular

levels of DA metabolites 3,4-dihydroxyphenylacetic acid

(DOPAC) and homovanillic acid (HVA), however, in a less

consistent way. Systemic administration of the s1 receptor

agonists (þ )-SKF-10,047, (^ )-pentazocine or DTG sig-

nificantly increased extracellular DOPAC levels [160,161].

Since the major proportion of extracellular DOPAC derives

from an intraneuronal pool of newly synthesized DA [259,

322], the authors suggested that increases in extracellular

DOPAC induced by the s1 agonists reflected augmented DA

synthesis and metabolism. However, systemic adminis-

tration of the putative s1 receptor antagonist (S)-(2 )-[4-

hydroxy-4-(3,4-benzodioxol-5-yl)-piperidin-1-ylmethyl]-3-

(4-methoxyphenyl) oxazolidin-2-one (EMD 57445) or the

local intranigral injection of DTG significantly increased

both 3,4-dihydroxyphenylacetic acid (DOPAC) and homo-

vanillic acid (HVA) levels in the striatum [15,256], which

could rather be consistent with decreased DA neurotrans-

mission by increased DA metabolism.

Only one study examined the effect of a s1 receptor

agonist directly on tyrosine hydroxylase activity in the rat

striatum [304]. Intranigral injection of DTG increased both

contralateral turning and tyrosine hydroxylase activity in a

parallel manner. However, no other, more selective s1

receptor agonists and antagonists were tested, in order to

selectively involve the s1 receptor in this effect.

The neuromodulatory role of selective s1 receptor

ligands on dopaminergic activity was examined using

electrophysiological studies on either the A9 meso-striatal

or the A10 meso-cortico-limbic dopaminergic pathways.

Both the firing activity and number of active neurons were

determined using acute or repeated treatments. The firing

activity of dopaminergic neurons was increased by acute

administration of the s1 receptor agonists (þ )-pentazocine

and (þ )-SKF-10,047 and decreased by the other agonists

DTG or (þ )-3-PPP, putatively acting as inverse agonists

[44,71,73,266,267]. The s1 receptor antagonists BMY-

14,802 or 4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-[4-

(1,2,4-triazol-1-yl)butyl]piperidine citrate (E-5842) failed

to affect A9 and A10 neurons but BMY-14,802 reversed the

inhibition of the firing activity of A9 neurons induced by a

prior administration of (þ )-3-PPP [66,178,212,242,297,

323,324]. In terms of number of spontaneously active A9 or

A10 dopaminergic neurons, DTG, (þ )-pentazocine, igme-

sine were without effect but the selective agonist SA4503

showed a differential effect by decreasing the number of

active neurons in A9 and increasing it in A10 pathway [181,

323]. Under microiontophoretic administration in A9 or A10,

the agonists (þ )-SKF-10,047 and igmesine did not show

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527 503

any effect [70,71,83]. Results using s1 receptor antagonists

are particularly inconsistent since the number of active

dopaminergic neurons was increased by SR 31,742A [213],

decreased by rimcazole [212] and unaffected by E-5842

[242]. Finally, following chronic administration, the s1

agonist SA4503 increased whereas the s1 antagonists

BMY-14,802 and E-5842 reduced the number of active

dopaminergic neurons in A10 but not in A9 pathway [71,181,

212,242,297].

From these data, it is clear that the use of drugs more or

less selective for the s1 receptor and different administration

procedure led to marked inconsistencies among studies.

However, s1 receptor ligands seems to influence the electric

activity of the dopaminergic neurotransmission with a

different effect on the A9 or A10 pathways and through a

putatively complex mechanism that remains to be

determined.

The modulation exerted by s1 receptor ligands on

dopaminergic neurons may involve both a direct or indirect

interaction through potentiation of the responses of

dopaminergic neurons to NMDA. The selective s1 receptor

ligands 2-[4-(4-methoxy-benzyl)piperazin-1-yl-methyl]4-

oxo[4H ]-benzo-thiazolin-2-one (S-21377), systemically

administered, and 2[(4-benzyl piperazin-1-yl)methyl]

naphthalene (S-21378), iontophoretically applied, slightly

increased the spontaneous firing rate and potentiated the

NMDA-induced neuronal activation of dopaminergic neur-

ons in the A9 and A10 regions [83]. The systemic

administration of igmesine, (þ )-pentazocine or DTG, or

microiontophoretic applications of igmesine, produced a

significant increase of NMDA-induced neuronal activation

in the nucleus accumbens. The drugs also increased

significantly the suppressant effect of dopamine on

NMDA and kainate-induced activation of accumbens

neurons. In the caudate nucleus, (þ )-pentazocine, but not

igmesine, potentiated slightly the neuronal response to

NMDA. These observations suggested that s1 receptors

may affect, but differentially, the glutamate NMDA

neurotransmission in the terminal and origin regions of

the mesolimbic and nigrostriatal dopaminergic systems

[83].

The regulation of NMDA-stimulated [3H]dopamine

release by s1 receptor ligands was also characterized

using superfused rat striatum slices by Gonzalez-Alvear

and Werling [79,80]. Low concentrations of the s1 receptor

agonists (þ )-pentazocine or BD737 inhibited the NMDA-

stimulated [3H]DA release in a concentration-dependent

manner. The s1 receptor antagonist DuP 734, haloperidol,

and N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrro-

lidinyl) ethylamine (BD1008) reversed the inhibition of

stimulated release by (þ )-pentazocine and BD737. Further-

more, BD737 and (þ )-pentazocine inhibited the stimulated

release in the presence of tetrodotoxin, suggesting that s1

receptors regulating DA release are located on dopamin-

ergic nerve terminals [80]. Attenuation by (þ )-pentazocine

of the NMDA-induced [3H]DA release was also observed

from rat hippocampal slices [37].

There is thus a growing body of evidence indicating that

selective s1 receptor ligands could exert a potent modu-

lation of dopaminergic systems directly or indirectly,

through modulation of NMDA receptors.

2. Cocaine addiction

Drug addiction has been defined as a chronic relapsing

brain disorder [142,196,197] characterized by a loss of

control over drug intake. The definition of substance

dependence is basically equivalent to the term addiction

which is used by the American Psychiatric Association to

describe symptoms such as compulsion to take a drug with a

loss of control to limit intake [7]. The motivating factors for

the development and persistence of drug addiction can be

divided into four different aspects of reinforcement: positive

reinforcement, negative reinforcement, conditioned positive

reinforcement and conditioned negative reinforcement

[311]. The definition of a reinforcer can be stated as any

kind of event that will increase the probability of response.

Cocaine is a highly addictive substance that is abused

worldwide [95,302]. Cocaine acts as a potent positive

reinforcer in laboratory animals [133,209,269,317]. While

cocaine inhibits the transport of serotonin (5-HT), norepin-

ephrine and dopamine (DA), it is widely accepted that the

addictive and reinforcing actions of cocaine are the result of

the drug’s ability to block the reuptake of DA by inhibiting

the dopamine transporter (DAT) and, thereby, increasing

DA neurotransmission [139,204,228,318].

2.1. Current investigations for pharmacotherapy to cocaine

addiction

A major goal of drug of abuse research is to develop

effective treatment strategies. One strategy for the treatment

of drug addiction focuses on the use of compounds that

substitute for the actions of the primary drug of abuse but

have a longer duration of action paired with lower intrinsic

abuse potential and lower toxic side effects [138,239]. In

addition to substituting for the primary effect of the drug of

abuse, the criteria for suitability as an agonist therapeutic

drug include slow onset of action and long-lasting effects

with a slow offset of action. Methadone, for example, while

supporting self-administration by rats [309] and monkeys

[268], is an effective agonist treatment drug for heroin

addiction [138]. Methadone can substitute for the reinforc-

ing effects of heroin and has long lasting effects when

administered orally in humans, without producing a

rush-like phenomenon that contributes critically to abuse

liability [138].

The efforts to develop a pharmacotherapy for the

treatment of drug dependence comes from the observation

that, especially in the case of opiates, for the majority of

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527504

patients, a drug-free approach was not effective [137]. It

must be emphasized, however, that to effectively manage an

addictive disease, any pharmacotherapy should be con-

ducted in combination with very supportive medical and

psychological supervision [137,138].

If one recognizes the evidence that chronic drug use

produces long lasting changes in the brain [1–3], searching

for a drug that would work to reverse the ‘chemical lesion’

induced by the compulsive intake of the drug of abuse

would be the most logical way in seeking therapeutic

medications. Moreover, an efficient pharmacological agent

for the treatment of cocaine addiction should block the acute

reinforcing and euphorogenic effect of cocaine, and

suppress the profound craving associated with the cocaine

abstinent state which leads to relapse [137]. In general, the

pharmacotherapies considered to treat dependence meet one

or more of the following criteria [126]: reduction of the risk

of addiction; reduction of the factors that promote behavior

associated with drug addiction; reduction in morbidity and

mortality associated with addiction; reduction of the use of

the drug and/or abstinence from the drug; treatment of the

symptoms associated with withdrawal and finally, preven-

tion of relapse. The following section will briefly review the

current directions of pharmacotherapy research.

A disorder such as cocaine addiction is very complex and

different preclinical directions have then been taken to try to

find an efficient treatment. Because of the link between

cocaine’s addictive liability and the DA reward/reinforce-

ment circuitry of the forebrain [133], many treatment

strategies have logically targeted the DA system. In

addition, since cocaine addiction involves other neurotrans-

mitter systems or even neuroendocrine dysregulations,

present strategies also focus on glutamatergic, 5-HT, opioid

or corticotropin-releasing hormone (CRH).

2.1.1. Strategies targeting DA receptors

The pre-clinical approach to seek treatment for cocaine

addiction has been focused on the three DA receptor

subtypes considered to be implicated in cocaine reinforce-

ment, namely D1, D2 and D3 receptors. Different pharma-

cological studies have been performed to characterize the

effects of these receptors.

The D1 and D2 receptor subtypes are widely distributed

throughout the brain in regions such as the striatum (caudate

putamen and nucleus accumbens), olfactory bulb, medial

pre-frontal cortex, substantia nigra and amygdala [296,303],

and have been demonstrated to be involved in mediating the

reinforcing effects of cocaine [18]. The D1 antagonists, such

as SCH 23390 and SCH 39166 attenuate the reinforcing

effect of cocaine [26] and reduce cocaine seeking behavior

in rats [43,306]. Other specific D1 agonists (e.g. SKF 82958)

attenuate the priming effect of cocaine in rats on a model of

cocaine relapse, increase the latency of cocaine self-

administration initiation and substitute for some of the

reinforcing effects of cocaine [54,250]. In contrast, D2

agonists such as quinpirole and R(2 )-propylnorapomor-

phine hydrochloride (NPA) induce a robust and selective

reinstatement of cocaine seeking behavior by mimicking the

priming effects of cocaine [54,120,312]. D2 antagonists,

such as eticlopride and spiperone, decrease the reinforcing

effects of cocaine under different schedules of reinforce-

ment [27]. Altogether, these findings suggest that D2

agonists increase craving for cocaine in laboratory animals

while D1 agonists do not. In addition, the stimulation of D1-

like receptors plays an inhibitory role in relapse to cocaine

seeking-behavior suggesting that D1 agonists could possibly

be an efficient treatment to cocaine addiction [138].

D3 receptors, in sharp contrast with D1 and D2 receptors,

have a restricted pattern of expression in the brain but are

highly expressed in the shell of the nucleus accumbens [20,

59,143], well recognized to be a critical structure respon-

sible for the effects of drugs of abuse [6,27]. In rats trained

to self-administer cocaine intravenously, D3 agonists, such

as pramipexole, quinelorane or PD 128,907 and the D3

preferring agonist 7-OH-DPAT, increase the reinforcing

actions of cocaine [25,28]. Moreover, a recent study has

shown that a partial D3 agonist (BP 897) inhibits cocaine-

seeking behavior without having any reinforcing efficacy on

its own [211] making it a good candidate for successful

treatment against cocaine addiction [141]. However, as it

has been noted by Koob and Caine [130], further pre-

clinical studies must be done before any definitive

conclusion can be made.

2.1.2. Strategies using DA reuptake inhibitors

In the case of cocaine, therapeutic agents with indirect

agonist properties (e.g. reuptake inhibitors) are likely to be

more effective than direct dopamine receptor agonists

because of emetic and other side effects associated with

drugs of the latter class. Several pre-clinical trials have been

done approaching agonist therapy by blocking the DAT.

For example different DAT reuptake inhibitors such as

1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpro-

pyl)piperazine (GBR 12909), N-[1-(2-benzo(b )thiophenyl)-

cyclohexyl]piperidine (BTCP) and methylphenidate have

been selected in regards: (1) to their high DAT binding

affinity; (2) to their ability to substitute to the primary

effect of cocaine and, maybe, (3) to their ability to produce

longer lasting effects than cocaine [138,153,230,238].

Consistent with this approach to act directly on the DA

level in the synaptic cleft, are the recent findings showing

that the manipulation of DA concentrations in the nucleus

accumbens or the amygdala can modulate cocaine self-

administration in rats [100].

However, these findings are still inconclusive, especially

because of the abuse potential these compounds may

possess. Thus, many efforts are under way to develop a

type of drug that will work as an indirect DA agonist like

cocaine (i.e. DAT blocker) but that has a slow onset of

action and a long duration of action [34].

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527 505

2.1.3. Strategies focusing on 5-HT systems

There is an increase in the amount of data showing that

other neurotransmitter systems are involved in cocaine

addiction. The 5-HT system, for example, has been shown

to participate in the reinforcing actions of cocaine and is an

important component in the behavioral effects of cocaine in

animals [35,36,149,265,260,261] and humans [9,24,246,

300]. Specifically, it has been shown that 5-HT1B receptors

modulate the reward/reinforcement induced by DA reuptake

inhibitors [29,69,203]. In particular, the stimulation of these

receptors have been shown to enhance the reinforcing

actions of DA uptake inhibitors and to facilitate cocaine-

induced DA increases in the mesolimbic DA neurotrans-

mission [202–204]. Moreover, construction of combined

DAT and 5-HT transporter (5-HTT) double-knockout mice

demonstrate that animals with no DAT (DAT2/2) and

either one (5-HTTþ/2 ) or no 5-HTT allele (5-HTT2/2)

were not able to develop conditioned spatial preference

(CSP) for cocaine. On the contrary, mice with both (DATþ/

þ ) or only one wild type DAT allele (DATþ/2) and no 5-

HTT allele (5-HTT2/2) developed place preference for

cocaine [260]. Altogether, these data suggest that 5-HT

system could interact with DA system and contribute to the

reinforcing actions of cocaine.

These findings, therefore, lead to the conclusion that

drugs targeting both DA and 5-HT brain systems might

provide an effective approach to fight cocaine addiction.

2.1.4. Strategies using opioids compounds

The rationale of using opioid compounds for cocaine

addiction is that opiate pathways may be involved in some

of the effects of cocaine. It has been demonstrated that high

levels for both mu (m) and kappa (k) receptors can be found

in the caudate putamen and in the nucleus accumbens, in the

hypothalamus, the substantia nigra, the olfactory tubercules

and the amygdala. The densities of these opioid receptors

increase in the caudate putamen, nucleus accumbens and

other regions of the mesolimbic–mesocortical and nigro-

striatal dopaminergic systems where there are abundant

dopaminergics terminals, after binge pattern of cocaine

administration [13,89,189,262,289]. Consistent with the

hypothesis of the involvement of the opioid system in some

of the effect of cocaine are the findings showing that levels

of dynorphin peptides, natural endogeneous ligands of k and

m receptors are modified after cocaine treatment. Specifi-

cally, studies have shown that the mRNA levels of

dynorphin is increased after both single or binge pattern

of cocaine administration in regions abundant in dopamin-

ergic terminals [51,99,263,308]. Dynorphin peptides are

also enhanced following chronic cocaine treatment in the

caudate putamen, nucleus accumbens, substantia nigra and

the ventral tegmental area [255], and can lower tuberoin-

fundibular dopaminergic tone through k and maybe m

opioid receptors [136]. Therefore, several studies investi-

gated the use of opioid compounds on some of the effects of

cocaine. For instance, compounds such as opioid antagonist

(naltrexone), partial m-opioid agonist (buprenorphine) and k

opioid agonists (e.g. ethylketocyclazocine, trans-3,4-

dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-ben-

zene acetamide (U-50,488H)) have been shown to modify

cocaine self-administration [76,134,175–177,191]. As a

particular example, buprenorphine has been shown to

attenuate the reinforcing effects of cocaine in animals and

humans [48,175–177]. Therefore, a number of several

studies are consistent with the idea that both DA and

endogeneous opiate receptor systems are important modu-

lators of the reinforcing effects of cocaine leading then to

other approaches towards a pharmacotherapy for cocaine

addiction.

2.1.5. Strategies using glutamate receptor antagonists

Earlier studies have shown that both acute and

intermittent cocaine administration increase glutamate

concentrations in the nucleus accumbens [210,258], a

brain region associated with the reinforcing and locomotor

effects of cocaine [131,310]. In addition to dopaminergic

innervation, this brain structure receives glutamatergic input

from several regions such as the pre-frontal cortex,

amygdala and hippocampus [180] and a growing body of

evidence suggests that these two neurotransmitter systems

may interact to produce some of cocaine’s effects. While it

is widely accepted that elevation of DA in the nucleus

accumbens is responsible for the stimulant effects of

cocaine, other studies have shown that both ionotropic and

metabotropic glutamate receptors (mGluRs) are involved in

the behavioral effects of psychostimulants [122,274,293],

opening another original approach to combating cocaine

addiction.

Consistent with the hypothesis of targeting the

glutamatergic system are several studies showing that

the use of N-methyl-D-aspartate (NMDA) antagonists such

as dizocilpine (MK-801) resulted in the blockade of

behavioral sensitization induced by cocaine [110,117,314].

Other studies using operant behavior (i.e. cocaine self-

administration) also demonstrated the implication of

glutamate in the reinforcing effects of cocaine. For example,

Schenk et al. [249] demonstrated that rats that received pre-

treatement with dizocilpine failed to acquire cocaine self-

administration. Moreover, another study on an animal

model of relapse showed that intra-accumbens treatment

with the potent competitive a-amino-3-hydroxy-5-methyl

isoxazole-4-propionic acid (AMPA)/kainate receptor

antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)

completely inhibited cocaine-induced reinstatement of

drug-seeking behavior in rats [50]. Finally, a recent study

by Chiamulera et al. [38] showed that mice lacking the

mGluR5 gene cannot self-administer cocaine, do not show

an increase of locomotor activity following cocaine

injection, while cocaine-induced an increase of DA levels

in the nucleus accumbens similar to the wild-type mice.

Therefore, this type I mGluR normally highly expressed in

the nucleus accumbens [276] seems to play an important

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527506

role in the stimulant and reinforcing effects of cocaine.

Altogether, these studies demonstrate that the glutamatergic

receptor system plays an important role in the establishment

of cocaine as an effective reinforcer and that the use of

glutamate antagonists could be an original approach to treat

cocaine abuse.

2.1.6. Strategies using CRH antagonists

Activation of the hypothalamic-pituitary-adrenocortical

(HPA) axis is the main neuroendocrine response to

particular environmental challenge, such as stress. Hor-

monal changes correspond to increased peripheral and

central glucocorticoid levels and release of CRH in different

brain structures. These hormonal responses counteract the

altered homeostatic balance of the organism in response to

stress. Activation of the HPA axis is involved in different

phases of drug addiction [245]. For instance, acute cocaine

administration induces activation of the HPA axis, release

of adrenocorticotropin hormone (ACTH) and increased

plasma corticosterone levels [182,229]. This activation of

HPA axis may involve hypothalamic CRH release, since

pre-treatement with a CRF antiserum or a CRH antagonist

blocked the cocaine-induced ACTH release and coritoster-

one response [229,244]. Moreover, cocaine was found to

release CRH from hypothalamic explants in vitro [33].

Thus, the acute effect of cocaine on the HPA axis involves

CRH release, notably from the hypothalamus and activation

of CRH receptors. The chronic administration of cocaine

leads to a sustained increase in basal activity of the HPA

axis [245]. In turn, stimulation of CRH is also involved in

the development of behavioral sensitization to cocaine [52,

53] and in the acquisition of cocaine-induced self-

administration [77]. Finally, CRH systems are involved in

the affective and somatic symptoms of drug withdrawal

[135]. Cocaine withdrawal induces anxiogenic-like

responses in rats, that may be mediated by increased CRH

release in the hypothalamus, basal forebrain and amygdala

[226,243]. In conclusion of this brief overview, hypothala-

mic as well as extrahypothalamic CRH systems are involved

in the physiological neuroadaptations and behavioral

consequences of cocaine addiction and CRH antagonists

are proposed to be developed as new pharmacotherapies

against compulsive drug use.

Despite promising pre-clinical data, many of the

proposed approaches have clinical limitations, due notably

to the complex manifestations of cocaine addiction, to

limited efficacy or problems with side effects. Therefore,

there is still a need to investigate alternative strategies.

2.2. Animal models of behavior for reward and

reinforcement

In the effort to understand how positive reinforcers work,

several animal models of behavior have been used to

specifically measure the stimulating, rewarding and rein-

forcing effects of a psychostimulant such as cocaine.

2.2.1. Neuroadaptive changes associated with repeated

drug administration—sensitization

One of the effects of psychomotor stimulants is that

repeated administration of these drugs enhances many of

their effects. This phenomenon is known as sensitization or

reverse tolerance. Early findings with cocaine demonstrated

that repetitive intermittent treatment induced an augmenta-

tion of hyperactivity in different species [60,61,278]. Today,

these effects have been well documented and, in general,

these studies have shown that with repeated administration,

cocaine produces increased locomotor activity [111,114,

216], an increased intensity of stereotyped behavior [147,

281], and an enhancement of rotational behavior in animals

with unilateral 6-hydroxydopamine (6-OHDA) lesions in

the substantia nigra [84]. Sensitization may play a role in

addiction or in disorders such as drug craving [208,232] and

psychostimulant induced psychosis [65,214,215]. There-

fore, it has been an important issue to determine the

conditions that lead to sensitization and promote its

expression. For instance, it has been demonstrated that the

environment is an important parameter in expressing

sensitization to the psychomotor stimulant effects of cocaine

[14,23,205]. The amount of prior cocaine exposure required

for the development of behavioral sensitization and the

intensity of the sensitized response is strongly influenced by

environmental factors. A robust expression of sensitization

can be measured when the drug has been repeatedly paired

in the test environment [14,16,19,216,275,307]. However,

this behavioral sensitization can be suppressed if the

animals are tested in a different environment than the

treatment environment. This suggests, then, that sensitiz-

ation has taken place but was not expressed. Therefore, the

environmental stimuli associated with the drug adminis-

tration may be a critical factor which would determine

whether a given dose of drug may induce sensitization and

may have relevance for individual variations in the response

to the drug (including addiction), in humans.

2.2.2. Neuroadaptive changes associated with repeated

drug administration—conditioning

Another important phenomenon associated with inter-

mittent treatment of psychostimulants such as cocaine is

conditioning. Several studies have shown that repeated

pairing of cocaine with a particular environment produces a

robust conditioned locomotor response without the drug

[29,247,248]. CSP is a procedure commonly used with

rodents in order to study the affective (positive, neutral or

negative) effects of drugs [247,248]. This procedure is based

on a particular rodent’s behavior to move close to a stimulus

that has been previously paired with an incentive state

induced by a drug such as cocaine [247,248]. This procedure

presents advantages in comparison with a model of operant

responding such as self-administration. First, this model

allows the rewarding and the aversive effects of a drug to be

measured. These particular effects of cocaine, namely

rewarding and aversive, have been well characterized by

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527 507

Ettenberg et al. [68]. These authors demonstrated that

conditioning is largely dependent on the time the environ-

ment is paired with the rewarding effect of cocaine. Thus,

the animals will approach an environment associated with

the immediate positive effects of cocaine while they will

avoid an environment associated with the drug’s subsequent

aversive effects [67,68]. Second, the testing in this model of

behavior is performed when the animals are in a drug-free

state, permitting motivational effect of the drug to be

directly evaluated and not the direct pharmacological effect

of the drug by itself on behavior. Finally, in contrast to self-

administration studies, the testing is based only on the

motivation (expectation) of the animals to receive an

injection and obtain a reward while in self-administration

testing, there could be a confusion between the motivation

and consumption aspects of reinforcement. Altogether,

these observations suggest that drugs that attenuate or

block place preference induced by cocaine should have the

potential to develop some kind of treatment for cocaine

addiction in humans.

2.2.3. Drug discrimination

Drug discrimination is another paradigm of behavioral

pharmacology that was developed to assess the subjective

drug effects in animals. This paradigm has been designed to

train the animals to discriminate the injection of a particular

dose (training dose) of a particular drug (training drug) from

a vehicle injection. For example, in a drug discrimination

paradigm the animals can be food deprived and then trained

to press one of two levers for food in daily 15 min sessions

[46,127–129]. Some time before the sessions, the animals

are injected with either the drug or vehicle. After the drug

injection, the animals are required to press on the ‘drug

lever’ (i.e. the lever which will be responsible for the food

delivery) [47]. On the other hand, after the injection of

vehicle, the animals are required to press the ‘non-drug

lever’ (i.e. the other lever which had no scheduled

consequence after a drug injection). The training is

continued until the animals reliably press the appropriate

lever after drug or vehicle injection. After stable behavior is

reached, the animals can be used to perform tests of stimulus

generalization. Before the session the animals are adminis-

tered with either vehicle, different doses of the training drug

or any dose of any other agent [128,129]. During the test,

which of the two levers the animals select is measured. If

after the test treatment the animals press the drug lever,

there is considered to a stimulus generalization between the

training drug and the test treatment. It can then be concluded

that the test treatment produced a discriminative stimulus

similar to that of the training drug. On the contrary, if the

animal selects the non-drug lever after the test treatment, it

is considered to not produce a similar stimulus to that of the

training drug (i.e. there is no stimulus generalization) [47].

For instance, tests that are conducted with a lower dose of

the training drug than the training dose show a typical

generalization that can vary following the test dose (i.e. the

generalization does not occur with small doses and

progressively increases with larger doses) [47,129].

Cocaine, as a particular example of a drug of abuse, is a

stimulant known to produce subjective effects (e.g.

euphoria). Drug discrimination studies of cocaine in animals

have found discriminative effects to be very similar to the

subjective effects or perception of this drug in humans,

making the subjective effect of cocaine accessible for

experimental research [30,31,45].

2.2.4. Self-administration

The model of intravenous drug self-administration in

animals has been used to characterize whether different

psychostimulants will support self-administration and it has

been established that drug self-administration in animals

may be a predictor of abuse liability in humans [82,108].

The drug self-administration procedure has several advan-

tages when studying the reinforcing effects of a particular

drug. For example, self-administration of a drug by an

animal can provide a direct evaluation of the reinforcing

effect of a drug. The simplest, most common self-

administration technique used to characterize the reinforc-

ing property of a drug is the fixed ratio schedule of

reinforcement. In this model, the animals are trained to press

a lever a certain number of times, which is fixed throughout

the experiment, to receive a single infusion of the drug. On

this schedule of reinforcement, non-dependent animals can

maintain a stable intake of drug over time. The intake is

inversely related to the drug dose and the animals will then

self-administer more drug when the dose of the drug

decreases to accommodate as a compensatory response, the

effect of the difference dosage [319,320]. A compound like

cocaine, therefore, will induce a characteristic inverted U-

shaped dose-response function [97,153,204]. The dose-

effect function obtained in these conditions is very

consistent and can be used to characterize the pharmaco-

logical interaction of different compounds with cocaine. For

instance, an antagonist induces a shift of the dose response

to the right while an agonist produces a shift of the dose

response to the left [132,153,204,218].

To obtain a parameter of the reinforcing efficacy of a

drug, a different procedure of reinforcement such as a

progressive ratio is used. In a progressive ratio schedule of

reinforcement, the requirement (i.e. ratio) to obtain an

infusion of the drug is progressively increased until the

animal ceases to respond [8,225]. This termination of

responding is defined as the breaking point and corresponds

to the highest ratio reached in a session that results in the

delivery of a drug reinforcer [204,209,225]. Under this

schedule of reinforcement, the breaking point reflects the

motivation of the animal to self-administer a drug. The

breaking point is dose-dependent [8] and, as was described

for the fixed ratio schedule of reinforcement for cocaine, the

progressive ratio can then be used to test the effects of

different compounds on the reinforcing efficacy of cocaine.

For instance, it has been demonstrated that a decreased

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527508

breaking point induced by cocaine suggests an attenuation

of the reinforcing effects of cocaine, while an increased

highest completed ratio for cocaine self-administration

suggests an enhancement of cocaine’s reinforcing effects

[58,98,204]. In conclusion, the use of a progressive ratio and

a fixed ratio schedule of reinforcement provides a solid

foundation for the characterization of a drug that will

interact with the reinforcing action of cocaine.

2.2.5. Relapse models

Section 2.2.4 describes an animal model of behavior

where the actual chemical reinforcer, for example cocaine,

is present (i.e. the animals press a lever to obtain an infusion

of cocaine). However, drug addiction is a chronic relapsing

disorder and the environment previously associated with

cocaine is a critical factor that can produce intense drug

craving leading then to relapse [42,62,121,231,246,299].

Therefore, it is also important to create an animal model that

would investigate the implication of cues associated with

cocaine self-administration on cocaine-seeking behavior.

Several studies in animals have shown that stimuli

associated with the drug can reinstate extinguished

responding at a lever previously associated with cocaine

self-administration [55,74]. Other studies have confirmed

these earlier findings and have also demonstrated that (1) it

is possible to create a reliable animal model of ‘relapse’, (2)

drug-related cues are potent predictors for cocaine relapse,

(3) the effects of cocaine-related stimuli are resistant to

extinction and are still very efficient after an extended

period of abstinence, (4) DA neurotransmission is activated

in response to the cocaine cue in the basolateral amygdala,

nucleus accumbens and pre-frontal cortex and (5) the cue-

induced activation of these two limbic regions as well as

cocaine seeking-behavior can be reversed by specific D1

receptor antagonists [43,174,251,264,305,306]. Therefore,

such an animal model of relapse may serve as a useful tool

for the investigation of drug of abuse and relapse since this

model allows the independent examination of the con-

ditioned effects of cocaine, an important factor in cocaine

abuse.

The use of these different models of behavior associated

with the classical pharmacological approach to treat cocaine

abuse described earlier, demonstrate that the ‘chemical

lesion’ induced by cocaine is complex and involves several

brain sytems. Because of such a complex mechanism of

action, none of these pharmacological approaches seem to

provide definitive and conclusive results. However, recent

encouraging studies reported that another intracellular

receptor system, namely the s1 receptor, is involved in

cocaine’s effects. The following sections will describe in

detail the promising therapeutic approach targeting the s1

receptors in the brain.

3. Involvement of the s1 receptor in cocaine effects

The hypothesis for an involvement of the s1 receptor in

cocaine’s effects came from the initial observations showing

that: (i) cocaine binds to the s1 receptor at concentrations

close to those required for DAT inhibition (see Section 3.1)

suggesting that cocaine may interact simultaneously at both

targets; and (ii) s1 receptor ligands modulates the activity

and physiology of dopaminergic neurons, as detailed in

Section 1.4. Recent studies confirmed and extented such a

hypothesis by showing that the s1 receptor is involved in

numerous aspects of cocaine effects. This section will

summarize the most recent results and point out the

therapeutic opportunities of selective s1 receptor antagon-

ists as anti-cocaine agents.

3.1. Cocaine binding to the s1 receptor

The initial observation that cocaine, in addition to

binding to the DAT, displays a moderate but significant

affinity for the s receptor was made by Sharkey and

coworkers [254] (Table 1). Several authors were able to

reproduce similar results using various membrane prepar-

ations and radiotracers (Table 1). The affinity of cocaine for

the s receptor could be considered in the 2–7 mM range

[157,167,221,227]. Cocaine displays a marked stereo-

selectivity for the binding to s sites, since its (þ )-isomer

displays a lower affinity between 16 and 26 mM depending

on the binding assays and radiotracers [167,254]. In

addition, cocaine exhibits a 10-fold preference for the s1

subtype (about 3 mM), as compared to the s2 subtype (about

30 mM), suggesting that of the two s receptor subtypes,

most of cocaine’s action occurs through s1 receptors at in

vivo concentrations [157].

Cocaine thus interacts with the s1 receptor at a

concentration range that can be achieved in vivo. In

comparison, cocaine inhibits DA uptake with Ki values

reported in the 0.2–0.9 mM range [32,56,101,224,227].

Therefore, cocaine can be considered to show a 10-fold

preference for binding to the DAT vs. the s1 receptor. The

functional consequences of interacting with DAT and/or

sigma receptors may impact the type of behavior produced

Table 1

Relative potency of cocaine to inhibit in vitro binding to s1 receptors

Ki (mM) Radiotracer Animal species References

(2)-cocaine

1.7 [3H]haloperidol C57BL/6 mouse brain [227]

2.3 [3H](þ)-pentazocine Swiss Webster mouse brain [157]

2.7 [3H](þ)-SKF-10,047 Rat liver [167]

2.9 [3H](þ)-pentazocine Sprague Dawley rat brain [157]

3.8 [3H]haloperidol JAR cell homogenates [221]

4.2 [3H]haloperidol Solubilized extracts [221]

4.4 [3H]haloperidol JAR cell plasma [221]

6.7 [3H]haloperidol Rat brain [254]

(þ)-cocaine

16 [3H]haloperidol Rat brain [254]

26 [3H](þ)-SKF-10,047 Rat liver [167]

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527 509

by cocaine and thereby, the effectiveness of the pharmaco-

therapies that may be developed to target each of these sites.

Further studies are needed to determine the conditions under

which DAT and s1 receptors are equally or differentially

involved in the particularly complex behavioral profile

induced by cocaine.

3.2. Involvement of the s1 receptor in the acute stimulant

effects of cocaine

Cocaine, acting as a potent indirect DA agonist, induces

hyperactivity after acute injection. The physiological

relevance of the putative interaction of cocaine with the

s1 receptor was brought by showing that s1 antagonists

blocked the locomotor stimulant effect of cocaine [168,169,

179,313]. Selective s1 receptor antagonists, such as BMY-

14,802, rimcazole, 6-[6-(4-hydroxypiperidinyl)hexyloxy]-

3-methylflavone (NPC 16377), BD1008, BD1047 or 1-[2-

(3,4-dichloro-phenyl)ethyl]-4-methylpiperazine (BD1063)

decreased the locomotor stimulant effect of cocaine. Non-

selective ligands that present good affinity for both DA and

s1 receptors, such as haloperidol and (þ )-3-PPP did not

significantly affect the cocaine-induced locomotor effects.

Functional antagonism of s1 receptors can also be

achieved using either pharmacological antagonists or

antisense oligodeoxynucleotides. While pharmacological

antagonists act by competing with cocaine for access to s1

receptors, antisense oligodeoxynucleotides deplete the

number of s1 receptors that are available for cocaine

binding by interfering with the synthesis of new receptor

proteins. Two different antisense oligodeoxynucleotides

against s1 receptors were designed: an 18-mer designed to

span the initiation codon region of a cDNA sequence for s1

receptors was used as the antisense oligodeoxynucleotide

[124], and a 21-mer designed to target areas 297 to 277

after the initiation codon of a cloned cDNA sequence for s1

receptors was used to knock down sigma receptors [123].

Mismatch and sense oligodeoxynucleotides, and vehicle

were used as controls (see Section 4.1). Indeed, treatment

with either of the two different antisense oligodeoxynucleo-

tides significantly reduced the locomotor effects of cocaine

in mice [159].

Only one study reported the effects of a s receptor

agonist on the discriminative stimulus properties of cocaine

[286]. The effect of the non-selective s1/s2 receptor DTG

was examined in rats trained to discriminate cocaine in a

shock avoidance paradigm. DTG alone did not produce any

stimulus effects in common with cocaine but it significantly

shifted the stimulus-generalization curve for cocaine to the

left [286]. This observation suggested that activation of the

s1 receptor could facilitate the discriminative stimulus

properties of cocaine but it must be repeated with more

selective s1 receptor agonists. In addition it could be

expected that s1 receptor antagonists may impede the

discriminative stimulus effects of cocaine.

3.3. Involvement of the s1 receptor in the sensitization

induced by cocaine

Sensitization can be characterized by using repeated

administration of a stimulatory dose of cocaine or using pre-

administration of a single high dose [284,313]. The increase of

net activity measured over days or after the last administration

reveals that sensitization occurred. BMY-14,802, rimcazole or

SR-31742A, all acting as s1 receptor antagonists, attenuated

the development of cocaine-induced sensitization, on loco-

motion, rearing and stereotypy [284]. These antagonists were

also effective in attenuating the increased effect of a challenge

dose of cocaine administered alone after a 10-day abstinence

period, but failed, in this study, to affect the hyperactivity

induced by acute cocaine administration. Pre-treatment with

NPC 16377 before cocaine also blocked the acquisition of

sensitization. Interestingly, NPC 16377 failed to block the

expression of sensitization, when it was administered only

once before the last injection of cocaine in daily cocaine-

treated animals [313].

Functional changes ins1 receptors have also been observed

following cocaine-induced sensitization. Rats were sensitized

by repeated administration of cocaine and the effect of the s1

receptor agonist (þ)-3-PPP was examined after several days

of abstinence [4,285]. (þ)-3-PPP administration induced

increased rearing, stereotyped sniffing and head movements.

These augmented responses were antagonized by the s1

receptor antagonist BMY-14,802. These behavioral obser-

vations suggested that s1 receptor supersensitivity developed

during cocaine induced sensitization [285]. The mechanism of

the supersensitivity has still to be determined at the molecular

level. However, the changes in s1 receptor expression,

subcellular localization and functionality have to be exten-

sively examined in the different dopaminergic structures

involved in cocaine sensitization (caudate putamen, ventral

tegmental area, nucleus accumbens, amygdala, pre-frontal

cortex, etc.). A preliminary result was reported by Romieu

et al. [237], showing increased levels of s1 receptor mRNA in

the nucleus accumbens after a 4 days treatment with cocaine

using a place preference conditioning procedure (see Section

3.4).

Acquisition of behavioral sensitization involves acti-

vation of numerous early genes and intracellular cascades

[192]. The s1 receptor is believed to be an intracellular

calcium modulator located mainly on endoplasmic reticu-

lum and mitochondrial membranes in a resting state, and

translocated to plasma and nuclear membranes after

activation [91,188]. Therefore, it is possible that the

activated receptor could be involved in a facilitation of

the intracellular plasticity required for behavioral sensitiz-

ation processes.

3.4. Involvement of the s1 receptor in the cocaine-induced

rewarding properties measured using a CSP paradigm

The involvement of the s1 receptor on the rewarding

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527510

effect of cocaine was examined using the CSP procedure in

C57BL/6 mice [236]. During the 4 days conditioning

period, the animals received repeated administration of

cocaine and they were confined in one, drug-paired,

compartment of the box. After 6 h, the animals received

saline and were confined within the other, drug-unpaired,

compartment in order to follow an unbiased procedure

[236]. When tested 1 day after cessation of injections, the

animals show a significant increase of time spent in the

drug-paired compartment between the post- and pre-

conditioning session, indicating that animals associated

the environmental cue with drug injection. Pre-adminis-

tration of s1 receptor antagonists, namely NE-100 [199] or

BD1047 [154], were performed: (1) before each injection of

cocaine during the conditioning session, in order to show

effects on the acquisition of cocaine-induced CSP; or (2)

only before the post-conditioning test, in order to show

effects on the expression of cocaine-induced CSP. Both

acquisition and expression of cocaine-induced CSP was

significantly decreased by pre-treatment with either NE-100

or BD1047 [236,237].

A phosphorothioate-modified antisense oligodeoxy-

nucleotide, targeting s1 receptor mRNA, was administered

in mice intracerebroventricularly for 3 days. This treatment

led to a 58–60% reduction of the number of s1 sites in the

ipsilateral hippocampus, and to a 33–38% reduction in the

cortex, as assessed using Scatchard analyses of in vitro

binding experiments [163,164]. Control animals, receiving

the mismatch ODN, showed a significant cocaine-induced

CSP. Mice treated daily with the antisense ODN targeting

the s1 receptor failed to develop any cocaine-induced CSP

(Fig. 2) [236].

The s1 receptor agonists igmesine or 2-(4-morpholino)

ethyl-1-phenylcyclohexane-1-carboxylate hydrochloride

(PRE-084) failed to induce CSP when injected alone,

suggesting that the receptor is necessary but not sufficient to

induce CSP. In addition, the CSP induced by BTCP, a

selective dopamine reuptake inhibitor with a Ki value about

14 nM [294] for the DAT and 3.5 mM for the s1 receptor

[237], was blocked by treatments with the s1 receptor

antagonists similarly as observed with cocaine. This

observation suggested that the receptor activation is an

indirect consequence of the DAT inhibition induced by

cocaine but not a direct effect of the drug [237].

Repetitive treatment with cocaine during conditioning

increased s1 receptor mRNA expression in the nucleus

accumbens, but not in the striatum, pre-frontal cortex or

cerebellum, in parallel to marked locomotor sensitization

[237]. This observation confirmed previous data indicating

that cocaine administration led to s1 receptor behavioral

supersensitivity. The increased s1 receptor expression

within the nucleus accumbens is not surprising considering

the importance of this structure in the behavioral activation

and reward mechanisms [113]. Enhanced s1 receptor

expression in the nucleus accumbens only after 4 days of

treatment with cocaine confirmed the importance of this

particular target in the acquisition of cocaine-induced

behaviors and suggests that treatments allowing the down-

regulation of the expression of these receptors [102,236]

may, in parallel to pharmacological antagonism, alleviate

the intensity of cocaine’s effects.

3.5. By which mechanism could s1 receptor antagonists

block cocaine’s effects?

Precise brain structures, i.e. the ventral tegmental area,

nucleus accumbens or pre-frontal cortex, and the neuronal

circuitry involved is highly variable among each aspect of

the cocaine-induced plasticity [193,291]. Cocaine’s effects

after acute or repeated administration are due initially to

increase in extracellular monoamine concentrations, mainly

DA, by blockade of the reuptake of released monoamines

[228], and then to increase extracellular glutamate [112,222,

223,258]. The glutamate increase in each region appears

dependent on DA neurotransmission and subsequent to DA

receptor stimulation [112,223]. Both NMDA and AMPA

receptors have been implicated in cocaine’s effects. Co-

administration of numerous competitive or non-competitive

NMDA receptor antagonists, including dizocilpine, CPP,

CGS-19755, or (þ )-HA966, with cocaine blocked the acute

motor effects of cocaine, the induction of sensitization or

CSP [103,116–118,145]. Similarly, the AMPA receptor

antagonists DNQX or NBQX prevented the induction of

cocaine sensitization [116,145,146]. Recent electrophysio-

logical results also showed that a single cocaine adminis-

tration induces long-term potentiation of AMPA receptor-

mediated currents at excitatory synapses of DA neurons in

the ventral tegmental area [288]. This phenomenon is

selective to DA neurons in the VTA and is not observed

with GABA neurons or in the hippocampus. In addition, it is

blocked by dizocilpine and long-term potentiation is

occluded while long-term depression is enhanced by

cocaine. Thus, the cellular mechanisms underlying cocaine’s

primary effects at the dopaminergic synapse may be related

to potentiation of excitatory inputs onto DA neurons [288].

The s1 receptor could modulate the activity of dopa-

minergic neurons at different levels (Fig. 3). First, within the

ventral tegmental area, the glutamate receptor activity could

be modulated by s1 receptors present in the soma of

dopaminergic neurons (see Fig. 1F). Second, at the pre-

synaptic level, s1 receptor ligands could modulate the

efficacy of DA release. Third, within the post-synaptic

neuron s1 receptors are also present (see Fig. 1A–E) and

could be involved in the efficacy of the response to

dopaminergic receptors.

At present, evidence is lacking that s1 receptor ligands

exert an efficient modulation on the glutamate receptors

present in synapses of the ventral tegmental area and

affecting DA neuron activity. A s1 receptor-mediated

modulation of glutamate receptors has not yet been

documented in dopaminergic structures, but such an effect

has been demonstrated in pyramidal neurons of the CA3

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527 511

layer of the dorsal hippocampus [185,186]. The NMDA-

induced electric activity measured in vivo or the NMDA-

induced norepinephrine release from hippocampal slices

can be modulated by synthetic s1 receptor agonists or

endogenous substances acting through the s1 receptor

including neuroactive steroids [17,187]. The modulatory

action mediated by s1 receptors seems to be restricted to

NMDA receptors and not affecting the activity of AMPA

receptors [185,186].

The pre-synaptic effects of s1 receptor ligands on DA

release has been documented (see Section 1.4). Although a

very low density of s1 receptors at pre-synaptic sites could

be visualized, using immunohistochemistry for example [5,

207], functional evidence is accumulating that s1 receptors

exert a potent modulation on DA release (Fig. 3). In

superfusion studies, s1 receptor agonists such as (þ )-SKF-

10,047, (þ )-pentazocine or BD737 inhibit NMDA-

stimulated DA release from guinea pig or rat striatal [11,

78,80] or nucleus accumbens slices [10]. All of these effects

are TTX insensitive, confirming the localization of s1

Fig. 2. Inhibition of the s1 receptor expression using in vivo administration of oligodeoxynucleotides (ODN) antisense to the s1 receptor blocked acquisition of

the cocaine-induced conditioned place preference in C57BL/6 mice. (A) The antisense and mismatch ODN targeting the s1 receptor were designed as

previously described [163,164,238] and administered i.c.v. every 12 h. (B) Animals were cannulated on day 1, and injected at 11:00 and 23:00, between days 2

and 5 during the conditioning phase. They were confined for 30 min within the drug-paired compartment at 9:30 a.m. and within the drug-unpaired

compartment at 16:00. (C) Lack of acquisition of cocaine-induced CSP in s1 antisense ODN-treated animals, n ¼ 9–11 per group. **p , 0.01 vs the saline-

treated group. Adapted from Romieu et al. [236].

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527512

Fig. 3. Schematic representation of the mechanism of action of cocaine on the dopaminergic neuron of the mesolimbic pathway and the possible involvement of the s1 receptor. Both glutamatergic and

GABAergic afferents control the dopaminergic neuron within the ventral tegmental area (VTA), through either dendritic or somatic synapses [290]. Both NMDA and AMPA receptors are present at glutamatergic

synapses in the VTA, and mediates the cocaine-induced long-term potentiation (LTP) and long-term depression (LTD) [109,287]. In target areas, e.g. pre-frontal cortex (PfCtx), nucleus accumbens (NAc) or

amygdala, DA release is modulated by axo-dendritic glutamatergic and GABAergic afferents. Cocaine blocks the DAT and thus increases extracellular DA concentration, facilitating its effect on post-synaptic

DA receptors, mainly of the D1, D2 or D3 subtypes [290]. These receptors activate, through Gi/s protein coupling, either adenylyl cyclase (AC) or phospholipase C (PLC), thus increasing either cAMP or InsP3

second messengers within the cytosol of the post-synaptic neuron. InsP3 allows the activation of the InsP3 receptor present on the endoplasmic reticulum (ER) and the mobilization of intracellular Ca2þ pools.

Consequently, cAMP-dependent and Ca2þ-dependent kinases and transcription factors are activated, mediating the acute effects as well as longer duration neuroadaptive changes observed after cocaine exposure.

The s1 receptor is present within the soma of the dopaminergic neurons in the VTA, forming a trimeric complex with the InsP3 receptor via an ankyrin B anchor protein on the ER membrane [92]. Cocaine can

activate the s1 receptor through a direct or indirect, but not yet identified, interaction. After activation, the s1 receptor is translocated from the ER to the vicinity of the plasma membrane, where it could modulate

the activity of NMDA receptors. Such interaction may also happen within the pre-synaptic terminals in the NAc, since a s1 receptor-mediated modulation of the NMDA-stimulated DA release has been observed

[10–12]. The origin of s1 receptors present on the pre-synaptic membrane and their relative density are, however, still unknown. Within the post-synaptic neuron, the modulatory effect of s1 receptors may also

involve a translocation from the trimeric complex on the ER membrane to either plasma membrane, where it could decrease the activation of post-synaptic receptors such as opioid m or k receptors, or nuclear

membrane, where it could affect the transcription factors effects on gene expression. These hypotheses are built on present knowledge of the activation of s1 receptors in different cellular models and physiologic

responses, not limited to dopaminergic systems involved in cocaine addiction. However, it is proposed that this unique receptor plays a primordial facilitory role on neuronal interconnection in particular neuronal

pathways. The ability of cocaine to activate the s1 receptor may be in part responsible for its high addictive properties.

T.

Ma

urice

eta

l./

Neu

roscien

cea

nd

Bio

beh

avio

ral

Review

s2

6(2

00

2)

49

9–

52

75

13

receptors on pre-synaptic neurons [12]. A similar effect was

also observed on Kþ-stimulated DA release from rat nucleus

accumbens slices, where (þ )-pentazocine inhibited DA

release via s1 receptors [12]. The apparent contradiction

between the inhibition of DA release by synthetic s1

receptor agonists acting pre-synaptically and the expected

involvement of the s1 receptor in cocaine-induced indirect

dopaminergic agonist effects must be noticed. It may

suggest that cocaine does not act through pre-synaptic s1

receptors, or that synthetic compounds do not mimic the

action of cocaine or the endogenous ligand involved. s1

receptors could thus either potentiate or inhibit depolarization-

induced or NMDA receptor-mediated DA release in

dopaminergic neurons.

At the post-synaptic level in dopamergic structures, the

mechanism recently reported by Su and coworkers could be

proposed [91,92,270]. Activation of the s1 receptor by an

agonist causes the dissociation of a cytoskeletal adaptator

protein ankyrin from InsP3 receptors on the endoplasmic

reticulum, which then translocates to the plasma membrane

and nucleus. Such translocation leads to a local increase of

the intracellular Ca2þ concentration, which may affect

several intracellular components involved in the cellular

response, from enzymes to cytoskeletal proteins [270]. It is

thus proposed that cocaine could activate phospholipase C

b, via a post-synaptic DA receptor, purportedly a particular

subtype of D1 receptor [144,150,287,301]. Phospholipase C

activation would then be expected to increase InsP3, in turn

activating the InsP3 receptor on the endoplasmic reticulum.

Cocaine, through inhibition of the DAT and the resulting

increase of extracellular DA, could activate DA receptors

and, through an indirect activation, the s1 receptor. These

concomittent actions would lead to efficient intracellular

Ca2þ mobilizations, through the InsP3 receptor, and the

activation of kinases and transcriptions factors, permitting

the imprinting of cocaine effects. Blocking the s1 receptor

by selective antagonists would diminish the efficacy of the

InsP3 receptor-mediated intracellular Ca2þ mobilization to a

basal level, insufficient to activate second messenger

cascades [270].

After activation, the s1 receptor translocates to the

plasma membrane, where its precise action is still unclear.

The receptor could here possibly interact with opioid m or k

receptors. Indeed, the involvement of opioid receptors in

cocaine’s effects was detailed (see Section 2.1.4), and

several pieces of evidence suggest that s1 receptors exert a

potent modulation of the efficacy of opioid responses. First,

a tonically active anti-opioid s1 system exists within the

brain, which affect m, k1, k3, and d opioid receptors [39–41,

123]. Indeed, morphine analgesia induced by either

morphine, U-50,488H or naloxone benzoylhydrazone

could be antagonized by (2 )-pentazocine and (þ )-penta-

zocine equally well. The (þ )-pentazocine effect was

blocked by haloperidol or by an in vivo antisense strategy

targeting the s1 receptor. Haloperidol alone enhanced

morphine analgesia. Second, the scopolamine-induced

memory impairment in mice could be reversed by both

(þ )- and (2 )-pentazocine although not at the same dose

range [96]. Both effects could be antagonized by NE-100,

suggesting particularly that the anti-amnesic effects of (2 )-

pentazocine involved not only its effects at k-opioid

receptors but also an interaction with s1 receptors [96].

These observations suggest that in several brain structures

and opioid neuronal pathways, the s1 receptor mediates a

tonic anti-opioid action. In turn, in dopaminergic structures

the modulation of dopaminergic responses by opioid

systems, namely dynorphin peptide-containing neuronal

afferents, could be negatively modulated by s1 receptors at

the post-synaptic membrane. Dynorphin and synthetic

opioid agonists modulating negatively the reinforcing

effects of cocaine, s1 receptor agonists will in turn

positively modulate cocaine’s effects, as observed in vivo.

These anti-opioid s1 receptor effects in DA structures and

their proposed involvement in cocaine’s action has,

however, still to be demonstrated.

Alternatively, the s1 receptor could be involved in

second messenger pathways, activated by DA receptors

(Fig. 3). Indeed, cocaine has been reported to up-regulate

the cyclic adenosine 30-50-monophosphate (cAMP) pathway

through increase of adenylyl cyclase expression and

activity, increase in cAMP concentration and in cAMP-

dependent protein kinase A (PKA) activity [192]. The

cAMP response element-binding protein (CREB) is hyper-

phosphorylated which leads to dysregulation of the

expression of genes whose promoter contains CRE

sequences. Similarly, cocaine increases mitogen-associated

protein kinase (MAPK) pathways through activation of

post-synaptic dopaminergic neurons. These protein phos-

phorylation cascades lead to internalization of transcription

factors (Erk) within the nucleus, regulating gene expression.

These phenomena participate in short- and long-term

neuroadaptive changes, from rapid augmentations of

cellular activity to global modifications induced by long-

term cocaine exposure—sensitization and dependence—

and finally to withdrawal symptoms—drug craving and

relapse. At present, little information is available concern-

ing the nature of the genes whose expression is regulated by

the different aspects of cocaine addiction and the putative

involvement of the s1 receptor in these pathways has not yet

been examined. However, the regulatory role of the s1

receptor in intracellular Ca2þ mobilization from ER pools

suggests that it may modulate the activity of Ca2þ-

dependent enzymes, including MAPK. It remains to be

determined whether s1 receptor ligands affect AC activity,

cAMP levels, CREB phosphorylation, or even the phos-

phorylation activity of intracellular proteins through some

Ca2þ-dependent intracellular pathway. Interestingly,

repeated cocaine exposure modulates s1 receptor gene

expression, in the NAc [236]. Analysis of the gene promoter

sequence revealed that it is devoid of a CRE binding site for

CREB [216]. The increase in s1 receptor gene expression

could thus putatively result from the production of Fos and

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527514

Jun proteins, known to be highly expressed, as well as Fos-

related antigens (FRA) proteins, during cocaine exposure

[192], which, in turn, could bind to AP-1 sites identified on

the s1 receptor gene promoter [217].

The mechanism by which the s1 receptor is involved in

cocaine-induced behavioral responses remains to be fully

determined. The ubiquituous presence of the receptor,

within the origin as well as target structures of the

mesolimbic dopaminergic pathways or in pre- as well as

post-synaptic neurons within each of these structures,

suggests a multiplicity of neuromodulatory actions. Differ-

ent mechanisms could also underlie the s1 receptor

involvement in the acute effects of cocaine and after

short-term or long-term exposure. Furthermore, the s1

receptor has been involved in the toxic effects of cocaine,

such as convulsions and lethality, potentially through an

alternative mechanism involving not only the central but

also the peripheral s1 receptors.

4. Cocaine overdose

Abuse of cocaine can produce many adverse effects,

including convulsions and lethality, especially in overdose

situations. Previous efforts to develop pharmacotherapies to

manage overdose from cocaine have been limited in

success, and there are currently no effective treatments for

this medical emergency. The ability of cocaine to interact

with s1 receptors in key organ systems such as the brain,

heart and lung that are affected during a drug overdose

suggests that these proteins are viable targets for drug

development. Recent studies have validated this possibility

and the following sections summarize data demonstrating

that blocking cocaine’s access to s1 receptors, using either

pharmacological antagonists or antisense oligodeoxy-

nucleotides, attenuates the convulsive and lethal effects of

cocaine in rodents following an overdose.

4.1. Involvement of the s1 receptor in cocaine-induced

convulsions

The incidence of convulsions in individuals who abuse

cocaine is significant. Cocaine-induced convulsions can

result from exposure to large doses of cocaine, typically in

an overdose situation. In addition, convulsions can manifest

as a result of kindling, in which increased sensitivity to

cocaine is produced upon repeated exposure to the drug

eventually leading to seizures upon exposure to doses of

cocaine that had previously been subconvulsive. Thus far,

the implications of s1 receptors in cocaine-induced convul-

sions have only been studied in the former condition in

which antagonists have been shown to attenuate convulsions

resulting from a single, large dose of cocaine.

In these studies, pre-treatment of mice with s1 receptor

antagonists attenuated cocaine-induced convulsions. Tradi-

tional antagonists with significant affinity for s1 receptors,

such as haloperidol and BMY-14,802, were effective [158],

as were numerous novel ligands with high affinity for these

receptors. The largest characterized series of novel ligands

was BD1008 and its analogs with N-alkyl substitutions

(BD1060, BD1067), pyrrolodinyl ring modifications

(BD1047, LR172), conformational restrictions (BD1018,

BD1063, LR132, LR176) and aryl monosubstitutions (YZ-

011, YZ-016, YZ-018, YZ-027, YZ-028, YZ-029, YZ-030,

YZ-032, YZ-033); all of these compounds were shown to

significantly attenuate cocaine-induced convulsions in mice

[156–158,168,170] (Tables 2 and 3). In addition, the novel

ligands NPC 16377 and EMD 57445, which both possess

significant affinity for s1 receptors, also antagonized

cocaine-induced convulsions in mice [257,313]. Most

recently, rimcazole analogs with high affinity for s1

receptors have been described, SH3/24 and SH2/21, that

also protect against cocaine-induced convulsions [156].

However, rimcazole itself did not significantly attenuate

cocaine-induced convulsions in these studies, presumably as

a result of its low affinity for s1 receptors [156].

If antagonism of s1 receptors produces anti-cocaine

effects, then antisense oligodeoxynucleotides should pro-

duce a similar protective effect by reducing the number of

receptors that are available for cocaine binding. Indeed,

treatment with either of two different antisense oligodeoxy-

nucleotides against s1 receptors reduces the convulsive

effects of cocaine in mice, as compared with mismatch and

sense oligodeoxynucleotides, and vehicle were used as

controls (Fig. 4). Relative to the vehicle control, treatment

of mice with either of the antisense oligodeoxynucleotides

resulted in a significant reduction in the number of mice

convulsing when exposed to cocaine [157,159]. Receptor

binding studies demonstrated about a 40% reduction in the

number of s1 receptors in the brains of these antisense-

treated animals [157], suggesting that interfering with the

access of cocaine to brain s1 receptors impairs its

convulsive actions. In contrast, there was no significant

difference from the vehicle control when the mice were

treated with sense or mismatch oligodeoxynucleotides (Fig.

4C), suggesting the specificity of the effect to oligos

targeting the s1 sequence.

To better establish an association between antagonism of

s1 receptors and the prevention of the convulsive effects of

cocaine, a relationship between the ability of compounds to

interact with the receptor and their ability to produce their

protective actions was demonstrated in two separate studies.

In the first study, 12 aryl monosubstituted analogs of BD1008

with affinities for s1 receptor spanning a 1000-fold range

were tested for their ability to prevent cocaine-induced

convulsions in mice. There was a significant correlation

between the ability of the compounds to attenuate cocaine-

induced convulsions and their affinities for s1 receptors

[169]. In a second study, a similar relationship was

demonstrated with a series of rimcazole analogs. Again,

there was a significant relationship between the ability of the

rimcazole analogs to attenuate cocaine-induced convulsions

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527 515

and their affinities for s1 receptors [156]. Furthermore,

although many of the rimcazole analogs also had significant

affinities for dopamine transporters, this interaction could not

account for the protective actions of the compounds [156].

Therefore, not only does antagonism of s1 receptors attenuate

the convulsive effects of cocaine, the potencies of the

compounds in producing this protective effect appears related

to their binding affinities for s1 receptors.

Since antagonism of s1 receptors prevents the convulsive

effects of cocaine, then s1 receptor agonists should

exacerbate the effects of cocaine. Indeed, pre-treatment of

mice with DTG, a classical s receptor agonist with high

affinity for s1 receptors, shifts the dose-response curve for

cocaine-induced convulsions to the left, reflecting a

worsening of the convulsive effects of cocaine [158,168].

In addition, BD1052 and BD1031, two novel agonists with

high affinity for s1 receptors, also shift the dose-response

curve for cocaine-induced convulsions to the left [157,158].

The s1 receptor agonist SA4503 has also been reported to

prolong and enhance cocaine-induced convulsions in mice

[256], providing further evidence that s1 receptor agonists

worsen cocaine-induced convulsions.

The ability of s1 receptor agonists to worsen the

convulsive effects of cocaine, while s1 receptor antagonists

protect against it demonstrates the capacity to target this

receptor to achieve modulation of the actions of cocaine.

The specificity of this effect is suggested by the antisense

studies, which also show that antagonism of brain s1

receptors alone is sufficient to protect against the convulsive

effects of cocaine in mice. The relationship between the

ability of the antagonists to attenuate cocaine-induced

convulsions and their ability to interact with s1 receptors

also supports the potential importance of these sites in

understanding the behavioral toxicity of cocaine. Together,

Table 2

Relative potency of s1 ligands to attenuate cocaine-induced stimulant effects in rodents

Effect s1 antagonist Activity Active dose (or tested) Animal species Reference

Cocaine-induced locomotor increase

BMY-14,802 d 10 mg/kg Swiss Webster mouse [179]

¼ ba (15–30 mg/kg) Sprague-Dawley rat [284]

EMD 57445 d 1–10 mg/kg Wistar rat [151,257]

d 1–10 mg/kg Swiss mouse [151]

NPC 16377 d 40–60 mg/kg Swiss Webster mouse [313]

Rimcazole d 10 mg/kg Swiss Webster mouse [179]

b 5–20 mg/kg Wistar rat [151,257]

¼ (5–20 mg/kg) Swiss mouse [151]

SR 31742A d 2.5–10 mg/kg Swiss OF1 mouse [213]

¼ (5–15 mg/kg) Sprague-Dawley rat [284]

Haloperidol ¼ (0.03 mg/kg) Swiss Webster mouse [179]

(þ )-3-PPP ¼ (1 mg/kg) Swiss Webster mouse [179]

BD 1008 d 1 mg/kg Swiss Webster mouse [169]

BD1018 d 30 mg/kg Swiss Webster mouse [157]

BD1047 d 30 mg/kg Swiss Webster mouse [168]

BD 1063 d 30 mg/kg Swiss Webster mouse [169]

LR132 d 30 mg/kg Swiss Webster mouse [157]

LR 172 d 5 mg/kg Swiss Webster mouse [168]

DTG b 5 mg/kg Wistar rat [257]

SA4503 ¼ (1–10 mg/kg) Wistar rat [257]

Cocaine-induced stereotyped behaviors

BMY-14,802 ¼ (15–30 mg/kg) Sprague-Dawley rat [284]

SR 31742A ¼ (5–15 mg/kg) Sprague-Dawley rat [284]

Cocaine-induced sensitization

BMY-14,802 d 30 mg/kg Sprague-Dawley rat [284]

Rimcazole d 50 mg/kg Sprague-Dawley rat [284]

SR 31742A d 5–15 mg/kg Sprague-Dawley rat [284]

NPC 16377 d 40 mg/kg Swiss Webster mouse [313]

Acquisition of cocaine-induced conditioned place-preference

NE-100 d 10 mg/kg C57BL/6 mouse [236,237]

BD1047 d 1–10 mg/kg C57BL/6 mouse [236,237]

Antisense oligo d 2 £ 10 mg/day, 3 days C57BL/6 mouse [236]

Expression of cocaine-induced conditioned place-preference

NE-100 d 10 mg/kg C57BL/6 mouse [237]

BD1047 d 3–10 mg/kg C57BL/6 mouse [237]

a Variations remaining non-significant at the dose tested.

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527516

the data suggest s1 receptor antagonism as a potential

treatment strategy to replace the current practice of using

conventional anticonvulsants in emergency room situations

despite their lack of efficacy. However, additional studies

are needed to determine whether the observations made in

rodents will be generalizable to the human situation.

4.2. Involvement of the s1 receptor in cocaine-induced

lethality

Ideally, pharmacotherapies for the treatment of cocaine

overdose should protect against the ultimate toxic endpoint,

death. Death from a cocaine overdose follows neural,

cardiovascular, and respiratory dysregulation. While both

sigma receptor subtypes have been reported in the brain,

heart and lung, it is noteworthy that over 80% of sigma

receptors in the heart are of the s1 subtype [196]. Therefore,

together with the better affinity of cocaine for s1 receptors,

its prevalence in a key organ that is compromised during a

cocaine overdose is significant. The following sections

summarize data demonstrating the ability of s1 receptor

antagonists to attenuate cocaine-induced lethality in mice,

Table 3

Summary of s1 ligands that attenuate cocaine overdose in rodents. Convulsions are observed after 60 mg/kg i.p. cocaine and lethality after 125 mg/kg i.p.

cocaine in mice

Ligands Convulsions Lethality Reference

Activity Active dose (or tested) Activity Active dose (or tested)

Traditional ligands

Haloperidol d 0.1–5 mg/kg d 5–30 mg/kg [158]

Reduced haloperidol d 1–10 mg/kg d 5–10 mg/kg [158]

BMY-14,802 d 1–15 mg/kg d 30 mg/kg [158]

Rimcazole ¼ (1–60 mk/kg) ¼ (1–30 mk/kg) [158]

¼ (5–20 mg/kg) [257]

BD1008 and analogs

BD1008 d 1–30 mg/kg d 30 mg/kg [158]

N-alkyl substitutions

BD1060 d 1–30 mg/kg d 5–15 mg/kg [158]

BD1067 d 1–30 mg/kg d 1–30 mg/kg [158]

Pyrrolidinyl ring modifications

BD1047 d 1–40 mg/kg d 1 mg/kg [168]

LR 172 d 1–30 mg/kg d 1–5 mg/kg [168]

Conformational restrictions

BD1018 d 0.1–30 mg/kg d 5 mg/kg [157]

BD1063 d 1–40 mg/kg d 20–40 mg/kg [157]

LR132 d 1–30 mg/kg d 0.5–1 mg/kg [157]

LR176 d 0.1–30 mg/kg d 1–30 mg/kg [156]

Aryl monosubstitutions

YZ-011 d 0.1–30 mg/kg d 1 mg/kg [170]

YZ-016 d 0.1–30 mg/kg d n.d. [170]

YZ-018 d 0.1–30 mg/kg d n.d. [170]

YZ-027 d 0.1–30 mg/kg d 1 mg/kg [170]

YZ-028 d 0.1–30 mg/kg n.d. [170]

YZ-029 d 0.1–30 mg/kg n.d. [170]

YZ-030 d 5–30 mg/kg n.d. [170]

YZ-032 d 1–30 mg/kg d 15 mg/kg [170]

YZ-033 d 1–30 mg/kg n.d. [170]

Rimcazole analogs

SH3/24 d 0.1–15 mg/kg ¼ (0.1–5 mg/kg) [156]

SH2/21 d 0.1 mg/kg ¼ (1–30 mg/kg) [156]

Miscellaneous compound

NPC 16377 d 20–200 mg/kg ¼ (10–50 mg/kg) [313]

EMD 57445 d 1–3 mg/kg n.d. [257]

Antisense oligodeoxynucleotides

18-mer d 10 nmol/12 h, 4 £ n.d. [159]

21-mer d 10 mg/day, 4 days n.d. [157]

(297 to 277 after initiation codon). n.d. ¼ not determined.

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527 517

with a select group also showing efficacy when administered

as a post-treatment.

Pre-treatment of mice with a s1 receptor antagonist

reduces that number of mice that die following a normally

lethal overdose of cocaine. Traditional antagonists such as

haloperidol and BMY-14,802 possess significant affinity for

s1 receptors and also attenuate cocaine-induced lethality in

mice [157]. Numerous novel ligands with high affinity for

s1 receptors also prevent death from a cocaine overdose.

BD1008, as well as analogs with N-alkyl substitutions

(BD1060, BD1067), pyrrolodinyl ring modifications

(BD1047, LR172), conformational restrictions (BD1018,

BD1063, LR132, LR176) and aryl monosubstitutions (YZ-

011, YZ-027, YZ-032), all significantly attenuate cocaine-

induced lethality in mice [157,158,168,170]. Although the

rimcazole analogs SH3/24 and SH2/21 attenuated the

convulsive effects of cocaine, they were unable to prevent

cocaine-induced lethality. The reason for this has yet to be

conclusively determined, but it is most likely related to the

interaction of these compounds with other binding sites

including dopamine transporters [156]. Therefore, although

there may be individual compounds that deviate from the

overall pattern, when taken as a whole, the data suggest that

blockade of cocaine’s access to s1 receptors also reduces

the lethal effects of the drug.

Although the pre-treatment studies demonstrated that

deaths could be prevented if antagonists were already

occupying s1 receptors at the time of a cocaine overdose, to

be of practical use, the compounds must be protective when

administered after cocaine. Since death from a cocaine

Fig. 4. Inhibition of the s1 receptor expression using in vivo administration of oligodeoxynucleotides (ODN) antisense to the s1 receptor decreased cocaine-

induced convulsions in Swiss/Webster mice. (A) The antisense, sense and mismatch ODN targeting the s1 receptor were designed as previously described

[122]. (B) Animals were cannulated on day 1, and injected i.c.v. once a day on days 1, 2 and 4. (C) Significant reduction of the percentage of animals

convulsing after being administered cocaine, 60 mg/kg ip, n ¼ 5–11 per group. *p , 0.05 vs the saline-treated group. Adapted from Matsumoto et al. [156].

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527518

overdose can occur suddenly or with short latency, it is also

important for an anti-cocaine therapy to act quickly.

Therefore, it is significant that LR132 and YZ-011, novel

ligands possessing high affinity for s1 receptors, have been

shown capable of preventing cocaine-induced lethality even

when administered intraperitoneally as a post-treatment

[156,170]. In the post-treatment studies, the compounds

were administered after a cocaine overdose, following the

onset of convulsions at a time when deaths could be

expected within the next 2–4 min. In addition to LR132 and

YZ-011, another group of s1 receptor antagonists that could

not prevent death under the most rigorous post-treatment

conditions described here nonetheless exhibited increased

protective ability the earlier they were administered.

Therefore, administration routes that facilitate absorption

may enable additional s1 receptor antagonists to be

clinically relevant.

4.3. s1 receptors and mechanisms of cocaine-induced

behavioral toxicity

Together, the studies indicate that s1 receptor antagon-

ists have the potential to treat acute cocaine overdoses. The

data demonstrate that pharmacological antagonists and

antisense oligodeoxynucleotides against s1 receptors pre-

vent the convulsive and lethal effects of cocaine. In contrast,

agonists, sigma-inactive analogs, and mismatch or sense

oligodeoxynucleotides are devoid of these anti-cocaine

actions, suggesting that the ability to interfere with

cocaine’s access to s1 receptors is a key feature that affords

protection. The convulsive effects of cocaine appear

particularly linked to s1 receptors in the brain as

intracerebroventricular administration of s1 antisense

oligodeoxynucleotides alone was sufficient to protect

against the convulsive effects of cocaine. In contrast, the

lethal effects of cocaine appear to involve both central and

peripheral s1 receptors. Further mechanistic studies are

necessary to fully characterize the interaction between s1

receptors and cocaine during an overdose situation, as well

as with local anesthetic and other downstream modulatory

events that contribute to the toxic effects of cocaine.

5. Perspectives

Cocaine addiction is a compulsive use of the drug

following repeated exposure whatever the adverse side-

effects could be [193]. Chronic repeated drug exposure

induces in the brain, at the level of individual neurons or

neuronal circuits, adaptive changes altering the functional

properties of several neurotransmission systems. This is

illustrated by changes in activity or expression of diverse

cellular proteins, notably signaling proteins such as

receptors, G proteins, second messenger related enzymes

or protein kinases. Strategies aiming at counteracting the

development of cocaine addiction must thus take into

consideration the complex pattern of these changes

happening gradually, but rapidly and often irreversibly,

within the brain of addicted humans during the course of

repeated drug exposure.

In the present report, we reviewed behavioral and

biochemical evidence demonstrating that the s1 receptor

is involved in several cocaine-induced effects and adaptive

changes in the brain that are known to sustain the

development of addiction. The s1 receptor involvement

has been demonstrated using either selective antagonists or

antisense oligodeoxynucleotide administration in vivo. The

precise cellular mechanism of action of this intracellular

protein is at present only partially understood and

hypotheses are drawn mostly using in vitro models.

However, several important points remain to be determined,

including the precise ligand activating the s1 receptor after

cocaine administration, cocaine itself, or an endogenous

effector released directly or indirectly by cocaine and the

exact cellular processes regulated or affected by the s1

receptor activation.

Cocaine exposure can be grossly divided in: (i) effects

induced after acute administration; (ii) adaptive changes

induced after repeated drug exposure; (iii) adaptives

changes induced after long-term chronic drug exposure;

(iv) abstinence after drug withdrawal; and (v) overdosing.

As detailed above, the s1 receptor has been involved in the

hyperactivity—locomotor increase and stereotyped beha-

viors—induced by acute injection of cocaine; the sensitiz-

ation and reward developed after repeated injections of

cocaine; and the convulsions and lethality observed after

cocaine overdose. It appears thus that activation of the s1

receptor by cocaine is observed after acute drug exposure,

but also after repeated administration. Moreover, the idea

that the s1 receptor is an important and primary target of

cocaine action is sustained by the fact that apparently

different behaviors are affected by s1 receptor antagonists,

from locomotor response to convulsion or lethality.

However, the involvement of the s1 receptor has still to

be demonstrated in several other, major manifestations of

addiction, namely reinforcement/auto-administration para-

digms and relapse. No study at present addressed the

participation of the s1 receptor in either cocaine self-

administration or relapse to drug taking after an abstinence

period. If s1 receptors participate in these processes, then it

would appear as a key component of cocaine-induced

neuroadaptive changes.

Noteworthy, the neuronal substrates involved in cocaine

seeking behavior, underlying both self-administration and

relapse, may be similar as those involved in the sensitization

and reward processes. Particularly, DA neurotransmission

in the nucleus accumbens alters the rate of cocaine self-

administration [27,171], and relapse in drug seeking [251,

264]. It could thus be suggested that, within the nucleus

accumbens, the s1 receptor is activated by cocaine, not only

after a single exposure to the drug but also more sustainedly

after repeated and chronic exposure. The s1 receptor could

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527 519

then modulate both dopamine and glutamate neurotrans-

mission, through a precise cascade of biochemical events

that remains to be determined, and, in turn, contribute to the

development and expression of cocaine-induced

neuroadaptations.

The numerous and complex evidence of its implication in

cocaine addiction, its efficient neuromodulatory role on the

neurotransmission systems within the brain structures

primarily involved in cocaine neuroplasticity and its unique

mode of activation suggest that s1 receptors may constitute

a unique target for a future effective therapeutic strategy.

Acknowledgments

We heartily acknowledge Drs Tsung-Ping Su and

Francois Monnet for helpful discussions during the

preparation of this manuscript; Van-Ly Phan for providing

the immunohistochemical labeling of the s1 receptor in

dopaminergic structures; and Christina U. Lorentz for

assistance with preparation of the manuscript.

References

[1] Ahmed SH, Koob GF. Long-lasting increase in the set point for

cocaine self-administration after escalation in rats. Psychopharma-

cology 1999;146:303–12.

[2] Ahmed SH, Koob GF. Transition from moderate to excessive drug

intake: change in hedonic set point. Science 1998;282:298–300.

[3] Ahmed SH, Walker JR, Koob GF. Persistent increase in the

motivation to take heroin in rats with a history of drug escalation.

Neuropsychopharmacology 2000;22:413–21.

[4] Akimoto K, Hamamura T, Otsuki S. Subchronic cocaine treatment

enhances cocaine-induced dopamine efflux, studied by in vivo

intracerebral dialysis. Brain Res 1989;490:339–44.

[5] Alonso G, Phan VL, Guillemain I, Saunier M, Legrand A, Anoal M,

Maurice T. Immunocytochemical localization of the s1 receptor in

the adult rat central nervous system. Neuroscience 2000;97:155–70.

[6] Altman J, Everitt BJ, Glautier S, Markou A, Nutt D, Oretti R, Phillips

GD, Robbins TW. The biological, social and clinical bases of drug

addiction: commentary and debate. Psychopharmacology 1996;125:

285–345.

[7] American Psychiatric Association, Diagnostic and statistical manual

of mental disorders, 4th ed. Washington, DC: American Psychiatric

Press; 1994.

[8] Arnold JM, Roberts DCS. A critique of fixed and progressive ratio

schedules used to examine the neural substrates of drug reinforce-

ment. Pharmacol Biochem Behav 1997;57:441–7.

[9] Aronson SC, Black JE, McDougle CJ, Scanley BE, Jatlow P, Kosten

TR, Heninger GR, Price LH. Serotonergic mechanisms of cocaine

effects in humans. Psychopharmacology 1995;119:179–85.

[10] Ault DT, Radeff JM, Werling LL. Modulation of [3H]dopamine

release from rat nucleus accumbens by neuropeptide Y may involve

a sigma1-like receptor. J Pharmacol Exp Ther 1998;284:553–60.

[11] Ault DT, Werling LL. Differential modulation of NMDA-stimulated

[3H]dopamine release from rat striatum by neuropeptide Y and

sigma receptor ligands. Brain Res 1997;760:210–7.

[12] Ault DT, Werling LL. Phencyclidine and dizocilpine modulate

dopamine release from rat nucleus accumbens via sigma receptors.

Eur J Pharmacol 1999;386:145–53.

[13] Azaryan AV, Clock BJ, Rosenberger JG, Cox BM. Transient

upregulation of mu opioid receptor mRNA levels in nucleus

accumbens during chronic cocaine administration. Can J Physiol

Pharmacol 1998;76:278–83.

[14] Badiani A, Browman KE, Robinson TE. Influence of novel versus

home environments on sensitization to the psychomotor stimulant

effects of cocaine and amphetamine. Brain Res 1995;674:291–8.

[15] Bastianetto S, Rouquier L, Perrault G, Sanger DJ. DTG-induced

circling behaviour in rats may involve the interaction between s sites

and nigrostriatal dopaminergic pathways. Neuropharmacology 1995;

34:281–7.

[16] Bell K, Kalivas PW. Context-specific cross-sensitization between

systemic cocaine and intra-accumbens AMPA infusion in the rat.

Psychopharmacology 1996;127:377–83.

[17] Bergeron R, de Montigny C, Debonnel G. Potentiation of neuronal

NMDA response induced by dehydroepiandrosterone and its

suppression by progesterone: effects mediated via sigma receptors.

J Neurosci 1996;16:1193–202.

[18] Bergman J, Kamien JB, Spealman R. Antagonism of cocaine self-

administration by selective dopamine D(1) and D(2) antagonists.

Behav Pharmacol 1990;1:355–63.

[19] Bonate PL, Swann A, Silverman PB. Context-dependent cross-

sensitization between cocaine and amphetamine. Life Sci 1997;60:

PL1–PL7.

[20] Bouthenet ML, Souil E, Martres MP, Sokoloff P, Giros B, Schwartz

JC. Localization of dopamine D3 receptor mRNA in the rat brain

using in situ hybridization histochemistry: comparison with

dopamine D2 receptor mRNA. Brain Res 1991;564:203–19.

[21] Bowen WD, Walker JM, de Costa BR, Wu R, Tolentino PJ, Finn D,

Rothman RB, Rice KC. Characterization of the enantiomers of cis-

N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)cyclo-

hexylamine (BD737 and BD738): novel compounds with high

affinity, selectivity and biological efficacy at sigma receptors.

J Pharmacol Exp Ther 1992;262:32–40.

[22] Bowen WD. Sigma receptors: recent advances and new clinical

potentials. Pharm Acta Helv 2000;74:211–8.

[23] Browman KE, Badiani A, Robinson TE. The influence of

environment on the induction of sensitization to the psychomotor

activating effects of intravenouscocaine in rats is dose-dependent.

Psychopharmacology 1998;137:90–8.

[24] Buydens-Branchey L, Branchey M, Fergeson P, Hudson J,

McKernin C. Craving for cocaine in addicted users. Role of

serotonergic mechanisms. Am J Addict 1997;6:65–73.

[25] Caine SB, Koob GF, Parsons LH, Everitt BJ, Schwartz JC, Sokoloff

P. D3 receptor test in vitro predicts decreased cocaine self-

administration in rats. Neuroreport 1997;8:2373–7.

[26] Caine SB, Koob GF. Effects of dopamine D-1 and D-2 antagonists on

cocaine self-administration under different schedules of reinforce-

ment in the rat. J Pharmacol Exp Ther 1994;270:209–18.

[27] Caine SB, Koob GF. Effects of mesolimbic dopamine depletion on

responding maintained by cocaine and food. J Exp Anal Behav 1994;

61:213–21.

[28] Caine SB, Koob GF. Pretreatment with the dopamine agonist 7-OH-

DPAT shifts the cocaine self-administration dose-effect function to

the left under different schedules in the rat. Behav Pharmacol 1995;6:

333–47.

[29] Calcagnetti DJ, Keck BJ, Quatrella LA, Schechter MD. Blockade of

cocaine-induced conditioned place preference: relevance to cocaine

abuse therapeutics. Life Sci 1995;56:475–83.

[30] Callahan PM, Bryan SK, Cunningham KA. Discriminative stimulus

effects of cocaine: antagonism by dopamine D1 receptor blockade in

the amygdala. Pharmacol Biochem Behav 1995;51:759–66.

[31] Callahan PM, De la Garza 2nd R, Cunningham KA. Discriminative

stimulus properties of cocaine: modulation by dopamine D1

receptors in the nucleus accumbens. Psychopharmacology 1994;

115:110–4.

[32] Calligaro DO, Eldefrawi ME. High affinity stereospecific binding of

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527520

[3H]cocaine in striatum and its relationship to the dopamine

transporter. Membr Biochem 1988;7:87–106.

[33] Calogero AE, Gallucci WT, Kling MA, Chrousos GP, Gold PW.

Cocaine stimulates rat hypothalamic corticotropin-releasing hor-

mone secretion in vitro. Brain Res 1989;505:7–11.

[34] Carroll FI, Howell LL, Kuhar MJ. Pharmacotherapies for treatment

of cocaine abuse: preclinical aspects. J Med Chem 1999;42:

2721–36.

[35] Carroll ME, Lac ST, Asencio M, Kragh R. Intravenous cocaine self-

administration in rats is reduced by dietary L-tryptophan. Psycho-

pharmacology 1990;100:293–300.

[36] Carroll ME, Lac ST, Asencio M, Kragh R. Fluoxetine reduces

intravenous cocaine self-administration in rats. Pharmacol Biochem

Behav 1990;35:237–44.

[37] Chaki S, Okuyama S, Ogawa S, Tomisawa K. Regulation of NMDA-

induced [3H]dopamine release from rat hippocampal slices through

sigma-1 binding sites. Neurochem Int 1998;33:29–34.

[38] Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C,

Tacconi S, Corsi M, Orzi F, Conquet F. Reinforcing and locomotor

stimulant effects of cocaine are absent in mGluR5 null mutant mice.

Nat Neurosci 2001;4:873–4.

[39] Chien CC, Pasternak GW. Functional antagonism of morphine

analgesia by (þ )-pentazocine: evidence for an anti-opioid sigma 1

system. Eur J Pharmacol 1993;250:R7–R8.

[40] Chien CC, Pasternak GW. Selective antagonism of opioid analgesia

by a sigma system. J Pharmacol Exp Ther 1994;271:1583–90.

[41] Chien CC, Pasternak GW. Sigma antagonists potentiate opioid

analgesia in rats. Neurosci Lett 1995;190:137–9.

[42] Childress AR, McLellan AT, Ehrman R, O’Brien CP. Classically

conditioned responses in opioid and cocaine dependence: a role in

relapse? NIDA Res Monogr 1988;84:25–43.

[43] Ciccocioppo R, Sanna PP, Weiss F. Cocaine-predictive stimulus

induces drug-seeking behavior and neural activation in limbic brain

regions after multiple months of abstinence: reversal by D(1)

antagonists. Proc Natl Acad Sci USA 2001;98:1976–81.

[44] Clark D, Engberg G, Pileblad E, Svensson TH, Carlsson A, Freeman

AS, Bunney BS. An electrophysiological analysis of the actions of 3-

PPP enantiomers on the nigrostriatal system. Naunyn-Schmiedeberg’s

Arch Pharmacol 1985;329:343–4.

[45] Colpaert FC, Niemegeers CJ, Janssen PA. Discriminative stimulus

properties of cocaine: neuropharmacological characteristics as

derived from stimulus generalization experiments. Pharmacol

Biochem Behav 1979;10:535–46.

[46] Colpaert FC, Niemegeers CJ, Janssen PA. Theoretical and

methodological considerations on drug discrimination learning.

Psychopharmacologia 1976;46:169–77.

[47] Colpaert FC. Drug discrimination in neurobiology. Pharmacol

Biochem Behav 1999;64:337–445.

[48] Compton PA, Ling W, Charuvastra VC, Wesson DR. Buprenorphine

as a pharmacotherapy for cocaine abuse: a review of the evidence.

J Addict Dis 1995;14:97–114.

[49] Contreras PC, Quirion R, O’Donohue TL. Autoradiographic

distribution of phencyclidine receptors in the rat brain using

[3H]1-(1-(2-thienyl)cyclohexyl)piperidine ([3H]TCP). Neurosci

Lett 1986;67:101–6.

[50] Cornish JL, Kalivas PW. Glutamate transmission in the nucleus

accumbens mediates relapse in cocaine addiction. J Neurosci 2000;

20:RC89(1-5).

[51] Daunais JB, Roberts DC, McGinty JF. Cocaine self-administration

increases preprodynorphin, but not c-fos, mRNA in rat striatum.

Neuroreport 1993;4:543–6.

[52] De Vries AC, Pert A. Conditioned increases in anxiogenic-like

behavior following exposure to contextual stimuli associated with

cocaine are mediated by corticotropin-releasing factor. Psycho-

pharmacology 1998;137:333–40.

[53] De Vries AC, Taymans SE, Sundstrom JM, Pert A. Conditioned

release of corticosterone by contextual stimuli associated with

cocaine is mediated by corticotropin-releasing factor. Brain Res

1998;786:39–46.

[54] De Vries TJ, Schoffelmeer AN, Binnekade R, Vanderschuren LJ.

Dopaminergic mechanisms mediating the incentive to seek cocaine

and heroin following long-term withdrawal of IV drug self-

administration. Psychopharmacology 1999;143:254–60.

[55] de Wit H, Stewart J. Reinstatement of cocaine-reinforced responding

in the rat. Psychopharmacology 1981;75:134–43.

[56] Debler EA, Hashim A, Lajtha A, Sershen H. Ascorbic acid and

striatal transport of [3H]-1-methyl-4-phenylpyridine (MPPþ) and

[3H]dopamine. Life Sci 1988;42:2553–9.

[57] DeHaven-Hudkins DL, Hildebrand LM, Fleissner LC, Ward SJ.

Lack of correlation between s binding potency and inhibition of

contractions in the mouse vas deferens preparation. Eur J Pharmacol

1991;203:329–35.

[58] Depoortere RY, Li DH, Lane JD, Emmett-Oglesby MW. Parameters

of self-administration of cocaine in rats under a progressive-ratio

schedule. Pharmacol Biochem Behav 1993;45:539–48.

[59] Diaz J, Levesque D, Lammers CH, Griffon N, Martres MP, Schwartz

JC, Sokoloff P. Phenotypical characterization of neurons expressing

the dopamine D3 receptor in the rat brain. Neuroscience 1995;65:

731–45.

[60] Downs A, Eddy NB. The effect of repeated doses of cocaine on the

dog. J Pharmacol Exp Ther 1932;46:195–8.

[61] Downs A, Eddy NB. The effect of repeated doses of cocaine on the

rat. J Pharmacol Exp Ther 1932;46:199–200.

[62] Ehrman RN, Robbins SJ, Childress AR, O’Brien CP. Conditioned

responses to cocaine-related stimuli in cocaine abuse patients.

Psychopharmacology 1992;107:523–9.

[63] Ela C, Barg J, Vogel Z, Hasin Y, Eilam Y. Sigma receptor ligands

modulate contractility, Ca2þ influx and beating rate in cultured

cardiac myocytes. J Pharmacol Exp Ther 1994;269:1300–9.

[64] Ela C, Hasin Y, Eilam Y. Apparent desensitization of a sigma

receptor sub-population in neonatal rat cardiac myocytes by pre-

treatment with sigma receptor ligands. Eur J Pharmacol 1996;295:

275–80.

[65] Ellison G. Stimulant-induced psychosis, the dopamine theory of

schizophrenia, and the habenula. Brain Res Rev 1994;19:223–39.

[66] Engberg G, Wikstrom H. s-Receptors: implication for the control of

neuronal activity of nigral dopamine-containing neurons. Eur J

Pharmacol 1991;201:199–202.

[67] Ettenberg A, Geist TD. Animal model for investigating the

anxiogenic effects of self-administered cocaine. Psychopharma-

cology 1991;103:455–61.

[68] Ettenberg A, Raven MA, Danluck DA, Necessary BD. Evidence for

opponent-process actions of intravenous cocaine. Pharmacol Bio-

chem Behav 1999;64:507–12.

[69] Fletcher PJ, Korth KM. Activation of 5-HT1B receptors in the

nucleus accumbens reduces amphetamine-induced enhancement of

responding for conditioned reward. Psychopharmacology 1999;142:

165–74.

[70] Freeman AS, Bunney BS. The effects of phencyclidine (PCP) and the

enantiomers of N-allylnormetazocine (SKF 10,047) on midbrain

dopamine neuronal activity. Eur J Pharmacol 1984;104:287–93.

[71] Freeman AS, Zhang J. In vivo electrophysiological effects of ligands

for PCP and sigma receptors on midbrain dopaminergic neurons. In:

Kamenka JM, Domino EF, editors. Multiple sigma and PCP receptor

ligands: mechanisms for neuroprotection and neuromodulation? Ann

Arbor: NPP Books; 1992. p. 227–40.

[73] French ED, Ceci A. Non-competitive N-methyl-D-aspartate antag-

onists are potent activators of ventral tegmental A10 dopamine

neurons in the rat. Neurosci Lett 1990;119:159–62.

[74] Fuchs RA, Tran-Nguyen LT, Specio SE, Groff RS, Neisewander JL.

Predictive validity of the extinction/reinstatement model of drug

craving. Psychopharmacology 1998;135:151–60.

[76] Glick SD, Maisonneuve IM, Raucci J, Archer S. Kappa opioid

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527 521

inhibition of morphine and cocaine self-administration in rats. Brain

Res 1995;681:147–52.

[77] Goeders NE, Guerin GF. Effects of the CRH receptor antagonist CP-

154,526 on intravenous cocaine self-administration. Neuropsycho-

pharmacology 2000;23:577–86.

[78] Gonzalez GM, Werling LL. Release of [3H]dopamine from guinea

pig striatal slices is modulated by sigma1 receptor agonists. Naunyn-

Schmiedebergs Arch Pharmacol 1997;356:455–61.

[79] Gonzalez-Alvear GM, Werling LL. regulation of [3H]dopamine

release from rat striatal slices by sigma ligands. J Pharmacol Exp

Ther 1994;271:212–9.

[80] Gonzalez-Alvear GM, Werling LL. Sigma1 receptors in rat striatum

regulate NMDA-stimulated [3H]dopamine release via a presynaptic

mechanism. Eur J Pharmacol 1995;294:713–9.

[81] Graybiel AM, Besson MJ, Weber E. Neuroleptic-sensitive binding

sites in the nigrostriatal system: evidence for differential distribution

of sigma sites in the substantia nigra, pars compacta of the cat.

J Neurosci 1989;9:326–38.

[82] Griffiths RR, Bigelow GE, Henningfield JE. Similarities in animal

and human drug-taking behavior. In: Mello NK, editor. Advances in

substance abuse, vol. 1. Greenwich: JAI; 1980. p. 1–90.

[83] Gronier B, Debonnel G. Involvement of sigma receptors in the

modulation of the glutamatergic/NMDA neurotransmission in the

dopaminergic systems. Eur J Pharmacol 1999;368:183–96.

[84] Guan LC, Robinson TE, Becker JB. Sensitization of rotational

behavior produced by a single exposure to cocaine. Pharmacol

Biochem Behav 1985;22:901–3.

[85] Gudelsky GA. Biphasic effect of sigma receptor ligands on the

extracellular concentration of dopamine in the striatum of the rat.

J Neural Transm 1999;106:849–56.

[86] Guldelsky GA. Effects of s receptor ligands on the extracellular

concentration of dopamine in the striatum and prefrontal cortex of

the rat. Eur J Pharmacol 1995;286:223–8.

[87] Gundlach AL, Largent BL, Snyder SH. Autoradiographic localiz-

ation of sigma receptor binding sites in guinea pig and rat central

nervous system with (þ )3H-3-(3-hydroxyphenyl)-N-(1-propyl)pi-

peridine. J Neurosci 1986;6:1757–70.

[89] Hammer Jr. RP. Cocaine alters opiate receptor binding in critical

brain reward regions. Synapse 1989;3:55–60.

[90] Hanner M, Moebius FF, Flandorfer A, Knaus HG, Striessnig J,

Kempner E, Glossman H. Purification, molecular cloning, and

expression of the mammalian sigma1-binding site. Proc Natl Acad

Sci USA 1996;93:8072–7.

[91] Hayashi T, Maurice T, Su TP. Ca2þ signaling via sigma1-receptors:

novel regulatory mechanism affecting intracellular Ca2þ concen-

tration. J Pharmacol Exp Ther 2000;293:788–98.

[92] Hayashi T, Su TP. Regulating ankyrin dynamics: roles of sigma-1

receptors. Proc Natl Acad Sci USA 2001;98:491–6.

[93] Hellewell SB, Bowen WB. A sigma-like binding site in rat

pheochromocytoma (PC12) cells: decreased affinity for (þ )-

benzomorphans and lower molecular weight suggest a different

sigma receptor form from that of guinea pig brain. Brain Res 1990;

527:244–53.

[94] Hellewell SB, Bruce A, Feinstein G, Orringer J, Williams W, Bowen

WB. Rat liver and kidney contain high densities of s1 and s2

receptors: characterization by ligand binding and photoaffinity

labeling. Eur J Pharmacol 1994;268:9–18.

[95] Higgins ST. The influence of alternative reinforcers on cocaine use

and abuse: a brief review. Pharmacol Biochem Behav 1997;57:

419–27.

[96] Hoshino T, Hiramatsu M, Kameyama T, Nabeshima T. Improvement

of memory impairment by (þ )- and (2)-pentazocine via k-opioid

and/or s-receptors in mice. Soc Neurosci Abstr 2000;26:753.17.

[97] Howell LL, Wilcox KM. The dopamine transporter and cocaine

medication development: drug self-administration in nonhuman

primates. J Pharmacol Exp Ther 2001;298:1–6.

[98] Hubner CB, Moreton JE. Effects of selective D1 and D2 dopamine

antagonists on cocaine self-administration in the rat. Psychophar-

macology 1991;105:151–6.

[99] Hurd YL, Brown EE, Finlay JM, Fibiger HC, Gerfen CR. Cocaine

self-administration differentially alters mRNA expression of striatal

peptides. Brain Res Mol Brain Res 1992;13:165–70.

[100] Hurd YL, Ponten M. Cocaine self-administration behavior can be

reduced or potentiated by the addition of specific dopamine

concentrations in the nucleus accumbens and amygdala using in

vivo microdialysis. Behav Brain Res 2000;116:177–86.

[101] Hyttel J. Inhibition of [3H]dopamine accumulation in rat striatal

synaptosomes by psychotropic drugs. Biochem Pharmacol 1978;27:

1063–8.

[102] Itzhak Y, Alerhand S. Differential regulation of sigma and PCP

receptors after chronic administration of haloperidol and phencycli-

dine in mice. FASEB J 1989;3:1868–72.

[103] Itzhak Y, Stein I. Sensitization to the toxic effects of cocaine in mice

is associated with the regulation of N-methyl-D-aspartate receptors in

the cortex. J Pharmacol Exp Ther 1992;262:464–70.

[104] Itzhak Y, Stein I. Sigma binding sites in the brain; an emerging

concept for multiple sites and their relevance for psychiatric

disorders. Life Sci 1990;47:1073–81.

[105] Itzhak Y. Multiple affinity binding states of the sigma receptor: effect

of GTP-binding protein-modifying agents. Mol Pharmacol 1989;36:

512–7.

[106] Jansen KL, Faull RL, Dragunow M, Leslie RA. Distribution of

excitatory and inhibitory amino acid, sigma, monoamine, catechol-

amine, acetylcholine, opioid, neurotensin, substance P, adenosine

and neuropeptide Y receptors in human motor and somatosensory

cortex. Brain Res 1991;566:225–38.

[107] Jbilo O, Vidal H, Paul R, De Nys N, Bensaid M, Silve S, Carayon P,

Davi D, Galiegue S, Bourrie B, Guillemot JC, Ferrara P, Loison G,

Maffrand JP, Le Fur G, Casellas P. Purification and characterization

of the human SR 31747A-binding protein. A nuclear membrane

protein related to yeast sterol isomerase. J Biol Chem 1997;272:

27107–15.

[108] Johanson CE, Schuster CR. A choice procedure for drug reinforcers:

cocaine and methylphenidate in the rhesus monkey. J Pharmacol Exp

Ther 1975;193:676–88.

[109] Johnson SW, North RA. Two types of neurone in the rat ventral

tegmental area and their synaptic inputs. J Physiol 1992;450:

455–68.

[110] Kalivas PW, Alesdatter JE. Involvement of N-methyl-D-aspartate

receptor stimulation in the ventral tegmental area and amygdala in

behavioral sensitization to cocaine. J Pharmacol Exp Ther 1993;267:

486–95.

[111] Kalivas PW, Duffy P, DuMars LA, Skinner C. Behavioral and

neurochemical effects of acute and daily cocaine administration in

rats. J Pharmacol Exp Ther 1988;245:485–92.

[112] Kalivas PW, Duffy P. D1 receptors modulate glutamate transmission

in the ventral tegmental area. J Neurosci 1995;15:5379–88.

[113] Kalivas PW, Nakamura M. Neural systems for behavioral activation

and reward. Curr Opin Neurobiol 1999;9:223–7.

[114] Kalivas PW, Stewart J. Dopamine transmission in the initiation and

expression of drug- and stress-induced sensitization of motor

activity. Brain Res Rev 1991;16:223–44.

[115] Kanzaki A, Okumura K, Ujike H, Tsuchida K, Akiyama K, Otsuki S.

BMY-14802 reverses the reduction of striatal dopamine release

induced by (þ )-3-[3-hydroxyphenyl]-N-(1-propyl)piperidine.

J Neural Transm 1992;90:137–44.

[116] Karler R, Calder LD, Bedingfield JB. Cocaine behavioral sensitiz-

ation and the excitatory amino acids. Psychopharmacology (Berl)

1994;115:305–10.

[117] Karler R, Calder LD, Chaudhry IA, Turkanis SA. Blockade of

reverse tolerance to cocaine and amphetamine by MK-801. Life Sci

1989;45:599–606.

[118] Karler R, Calder LD. Excitatory amino acids and the actions of

cocaine. Brain Res 1992;582:143–6.

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527522

[119] Kekuda R, Prasad PD, Fei YJ, Leibach FH, Ganapathy V. Cloning

and functional expression of the human type 1 sigma receptor

(hSigmaR1). Biochem Biophys Res Commun 1996;229:553–8.

[120] Khroyan TV, Barrett-Larimore RL, Rowlett JK, Spealman RD.

Dopamine D1- and D2-like receptor mechanisms in relapse to

cocaine-seeking behavior: effects of selective antagonists and

agonists. J Pharmacol Exp Ther 2000;294:680–7.

[121] Kilgus MD, Pumariega AJ. Experimental manipulation of cocaine

craving by videotaped environmental cues. South Med J 1994;87:

1138–40.

[122] Kim JH, Vezina P. Metabotropic glutamate receptors in the rat

nucleus accumbens contribute to amphetamine-induced locomotion.

J Pharmacol Exp Ther 1998;284:317–22.

[123] King M, Pan YX, Mei J, Chang A, Xu J, Pasternak GW. Enhanced k-

opioid receptor-mediated analgesia by antisense targeting the s1

receptor. Eur J Pharmacol 1997;331:R5–R6.

[124] Kitaichi K, Chabot JG, Moebius FF, Flandorfer A, Glossmann H,

Quirion R. Expression of the purported sigma1 (s1) receptor in the

mammalian brain and its possible relevance in deficits induced by

antagonism of the NMDA receptor complex as revealed using an

antisense strategy. J Chem Neuroanat 2000;20:375–87.

[125] Klein M, Cooper TB, Musacchio JM. Effects of haloperidol and

reduced haloperidol on binding to sigma sites. Eur J Pharmacol

1994;254:239–48.

[126] Klein M. Research issues related to development of medications for

treatment of cocaine addiction. Ann NY Acad Sci 1998;844:75–91.

[127] Kleven MS, Assie MB, Koek W. Pharmacological characterization

of in vivo properties of putative mixed 5-HT1A agonist/5-HT(2A/

2C) antagonist anxiolytics. II. Drug discrimination and behavioral

observation studies in rats. J Pharmacol Exp Ther 1997;282:747–59.

[128] Kleven MS, Kamenka JM, Vignon J, Koek W. Pharmacological

characterization of the discriminative stimulus properties of the

phencyclidine analog, N-[1-(2-benzo(b)thiophenyl)-cyclohexyl]pi-

peridine. Psychopharmacology 1999;145:370–7.

[129] Koek W, Colpaert FC, Woods JH, Kamenka JM. The phencyclidine

(PCP) analog N-[1-(2-benzo(B)thiophenyl) cyclohexyl]piperidine

shares cocaine-like but not other characteristic behavioral effects

with PCP, ketamine and MK-801. J Pharmacol Exp Ther 1989;250:

1019–27.

[130] Koob GF, Caine SB. Cocaine addiction therapy—are we partially

there? Nat Med 1999;5:993–5.

[131] Koob GF, Sanna PP, Bloom FE. Neuroscience of addiction. Neuron

1998;21:467–76.

[132] Koob GF, Vaccarino F, Amalric M, Bloom FE. Positive reinforce-

ment properties of drugs: search for neural substrates. In: Engel L,

Oreland L, editors. Brain reward systems and abuse. New York:

Raven Press; 1987. p. 35–50.

[133] Koob GF. Drugs of abuse: anatomy, pharmacology and function of

reward pathways. Trends Pharmacol Sci 1992;13:177–84.

[134] Kosten T, Silverman DG, Fleming J, Kosten TA, Gawin FH,

Compton M, Jatlow P, Byck R. Intravenous cocaine challenges

during naltrexone maintenance: a preliminary study. Biol Psychiatry

1992;32:543–8.

[135] Kreek MJ, Koob GF. Drug dependence: stress and dysregulation of

brain reward systems. Drug Alcohol Depend 1998;51:23–47.

[136] Kreek MJ, Schluger J, Borg L, Gunduz M, Ho A. Dynorphin A1-13

causes elevation of serum levels of prolactin through an opioid

receptor mechanism in humans: gender differences and implications

for modulation of dopaminergic tone in the treatment of addictions.

J Pharmacol Exp Ther 1999;288:260–9.

[137] Kreek MJ. Goals and rationale for pharmacotherapeutic approach in

treating cocaine dependence: insights from basic and clinical

research. NIDA Res Monogr 1997;175:5–35.

[138] Kreek MJ. Opiate and cocaine addictions: challenge for pharma-

cotherapies. Pharmacol Biohem Behav 1997;57:551–69.

[139] Kuhar MJ. Molecular pharmacology of cocaine: a dopamine

hypothesis and its implications. Ciba Found Symp 1992;166:81–9.

[140] Largent BL, Gundlach AL, Snyder SH. Pharmacological and

autoradiographic discrimination of sigma and phencyclidine recep-

tor binding sites in brain with (þ )-[3H]SKF 10,047, (þ)-[3H]-3-[3-

hydroxyphenyl]-N-(1-propyl)piperidine and [3H]-1-[1-(2-thienyl)-

cyclohexyl]piperidine. J Pharmacol Exp Ther 1986;238:739–48.

[141] Le Foll B, Schwartz JC, Sokoloff P. Dopamine D3 receptor agents as

potential new medications for drug addiction. Eur Psychiatry 2000;

15:140–6.

[142] Leshner AI. Addiction is a brain disease, and it matters. Science

1997;278:45–7.

[143] Levesque D, Diaz J, Pilon C, Martres MP, Giros B, Souil E, Schott

D, Morgat JL, Schwartz JC, Sokoloff P. Identification, characteriz-

ation, and localization of the dopamine D3 receptor in rat brain using

7-[3H]hydroxy-N,N-di-n-propyl-2-aminotetralin. Proc Natl Acad Sci

USA 1992;89:8155–9.

[144] Lezcano N, Mrzljak L, Eubanks S, Levenson R, Goldman-Rakic P,

Bergson C. Dual signaling regulated by calcyon, a D1 dopamine-

receptor interacting protein. Science 2000;287:1660–4.

[145] Li Y, Hu XT, Berney TG, Vartanian AJ, Stine CD, Wolf ME, White

FJ. Both glutamate receptor antagonists and prefrontal cortex lesions

prevent induction of cocaine sensitization and associated neuro-

adaptations. Synapse 1999;34:169–80.

[146] Li Y, Wolf ME, White FJ. The expression of cocaine sensitization is

not prevented by MK-801 or ibotenic acid lesions of the medial

prefrontal cortex. Behav Brain Res 1999;104:119–25.

[147] Lienau AK, Kuschinsky K. Sensitization phenomena after repeated

administration of cocaine or D-amphetamine in rats: associative and

non-associative mechanisms and the role of dopamine in the

striatum. Naunyn-Schmiedebergs Arch Pharmacol 1997;355:531–7.

[148] Lishmanov YuB, Maslov LN, Naryzhnaya NV, Tam SW. Ligands

for opioid and s-receptors improve cardiac electrical stability in rat

models of post-infarction cardiosclerosis and stress. Life Sci 1999;

65:PL13–PL17.

[149] Loh EA, Roberts DCS. Break-points on a progressive ratio schedule

reinforced by intravenous cocaine increase following depletion of

forebrain serotonin. Psychopharmacology 1990;101:262–6.

[150] Mahan LC, Burch RM, Monsma FL, Sibley DR. Expression of

striatal D1 dopamine receptors coupled to inositol phosphate

production and Ca2þ mobilization in Xenopus oocytes. Proc Natl

Acad Sci USA 1990;87:2196–200.

[151] Maj J, Rogoz Z, Skuza G, Mazela H. Neuropharmacological profile

of EMD 57445, a s receptor ligand with potential antipsychotic

activity. Eur J Pharmacol 1996;315:235–43.

[152] Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE. The

effects of morphine- and nalorphine-like drugs in the nondependent

and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther

1976;197:517–32.

[153] Martin-Fardon R, Weiss F. N-[1-(2-benzo[b]thiophenyl)cyclo-

hexyl]-piperidine (BTCP) exerts cocaine-like actions on drug-

maintained responding in rats. Neuropsychopharmacology 2000;

23:316–25.

[154] Matsumoto RR, Bowen WD, Tom MA, Vo VN, Truong DD, De

Costa BR. Characterization of two novel sigma receptor ligands:

antidystonic effects in rats suggest sigma receptor antagonism. Eur J

Pharmacol 1995;280:301–10.

[155] Matsumoto RR, Bowen WD, Walker JM. Down-regulation of sigma

receptors by chronic haloperidol. Prog Clin Biol Res 1990;328:

125–8.

[156] Matsumoto RR, Hewett KL, Pouw B, Bowen WD, Husbands SH,

Cao JJ, Newman AH. Rimcazole analogs attenuate the convulsive

effects of cocaine: correlation with binding to sigma receptors rather

than dopamine transporters. Neuropharmacology 2001;41:878–86.

[157] Matsumoto RR, McCracken KA, Friedman MJ, Pouw B, de Costa

BR, Bowen WD. Conformationally restricted analogs of BD1008

and an antisense oligodeoxynucleotide targeting s1 receptors

produce anti-cocaine effects in mice. Eur J Pharmacol 2001;419:

163–74.

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527 523

[158] Matsumoto RR, McCracken KA, Pouw B, Miller J, Bowen WD,

Williams W, De Costa BR. N-alkyl substituted analogs of the s

receptor ligand BD1008 and traditional sigma receptor ligands affect

cocaine-induced convulsions and lethality in mice. Eur J Pharmacol

2001;411:261–73.

[159] Matsumoto RR, McCracken KA. Antisense oligodeoxynucleotides

against s1 receptors reduce the convulsive and locomotor stimu-

latory effects of cocaine in mice. Soc Neurosci Abst 1999;25:303.

[160] Matsuno K, Matsunaga K, Mita S. Increase of extracellular

acetylcholine level in rat frontal cortex induced by (þ )N-

allylnormetazocine as measured by brain microdialysis. Brain Res

1992;575:315–9.

[161] Matsuno K, Matsunaga KH, Mita S. Acute effects of s ligands on the

extracllular DOPAC level in rat frontal cortex and striatum.

Neurochem Res 1995;20:233–8.

[162] Maurice T, Lockhart BP. Neuroprotective and anti-amnesic

potentials of sigma (s) receptor ligands. Prog Neuropsychopharma-

col Biol Psychiatry 1997;21:69–102.

[163] Maurice T, Phan VL, Privat A. The anti-amnesic effects of sigma1

(s1) receptor agonists confirmed by in vivo antisense strategy in the

mouse. Brain Res 2001;898:113–21.

[164] Maurice T, Phan VL, Urani A, Guillemain I. Differential involve-

ment of the sigma1 (s1) receptor in the anti-amnesic effect of

neuroactive steroids, as demonstrated using an in vivo antisense

strategy in the mouse. Br J Pharmacol 2001;134:1731–41.

[165] Maurice T, Phan VL, Urani A, Kamei H, Noda Y, Nabeshima T.

Neuroactive neurosteroids as endogenous effector for the sigma1 (s1)

receptor: pharmacological evidence and therapeutic opportunities.

Jpn J Pharmacol 1999;81:125–55.

[166] Maurice T, Urani A, Phan VL, Romieu P. The interaction between

neuroactive steroids and the sigma1 (s1) receptor function:

behavioral consequences and therapeutic opportunities. Brain Res

Rev 2001;37:116–32.

[167] McCann DJ, Su TP. Solubilization and characterization of

haloperidol-sensitive (þ )-[3H]SKF-10,047 binding sites (sigma

sites) from rat liver membranes. J Pharmacol Exp Ther 1991;257:

547–54.

[168] McCracken KA, Bowen WD, de Costa BR, Matsumoto RR. Two

novel s receptor ligands, BD1047 and LR172, attenuate cocaine-

induced toxicity and locomotor activity. Eur J Pharmacol 1999;370:

225–32.

[169] McCracken KA, Bowen WD, Matsumoto RR. Novel s receptor

ligands attenuate the locomotor stimulatory effects of cocaine. Eur J

Pharmacol 1999;365:35–8.

[170] McCracken KA, Miller J, Bowen WD, Zhang Y, Matsumoto RR.

Brain s1 receptors are involved in the behavioral effects of cocaine.

NIDA Res Monogr 2000;180:291.

[171] McGregor A, Roberts DC. Dopaminergic antagonism within the

nucleus accumbensor the amygdala produces differential effects on

intravenous cocaine self-administration under fixed and progressive

ratio schedules of reinforcement. Brain Res 1993;624:245–52.

[172] McLean S, Weber E. Autoradiographic visualization of haloperidol-

sensitive sigma receptors in guinea-pig brain. Neuroscience 1988;25:

259–69.

[173] Mei J, Pasternak GW. Molecular cloning and pharmacological

characterization of the rat sigma1 receptor. Biochem Pharmacol

2001;62:349–55.

[174] Meil WM, See RE. Conditioned cued recovery of responding

following prolonged withdrawal from self-administered cocaine in

rats: an animal model of relapse. Behav Pharmacol 1996;7:754–63.

[175] Mello NK, Lukas SE, Mendelson JH, Drieze J. Naltrexone–

buprenorphine interactions: effects on cocaine self-administration.

Neuropsychopharmacology 1993;9:211–24.

[176] Mello NK, Mendelson JH, Lukas SE, Gastfriend DR, Teoh SK,

Holman BL. Buprenorphine treatment of opiate and cocaine abuse:

clinical and preclinical studies. Harv Rev Psychiatry 1993;1:

168–83.

[177] Mello NK. Preclinical evaluation of the effects of buprenorphine,

naltrexone and desipramine on cocaine self-administration. NIDA

Res Monogr 1991;105:189–95.

[178] Meltzer LT, Christoffersen CL, Serpa KA, Pugsley TA, Razmpour

A, Heffner TG. Lack of involvement of haloperidol-sensitive sigma

binding sites in modulation of dopamine neuronal activity and

induction of dystonias by antipsychotic drugs. Neuropharmacology

1992;31:961–7.

[179] Menkel M, Terry M, Pontecorvo M, Katz JL, Witkin JM. Selective s

ligands block stimulant effects of cocaine. Eur J Pharmacol 1991;

201:251–2.

[180] Meredith GE, Pennartz CM, Groenewegen HJ. The cellular frame-

work for chemical signalling in the nucleus accumbens. Prog Brain

Res 1993;99:3–24.

[181] Minabe Y, Matsuno K, Ashby Jr. CR. Acute and chronic

administration of the selective sigma1 receptor agonist SA4503

significantly alters the activity of midbrain dopamine neurons in rats:

an in vivo electrophysiological study. Synapse 1999;33:129–40.

[182] Moldow RL, Fischman AJ. Cocaine-induced secretion of ACTH,

beta-endorphin and corticosterone. Peptides 1987;8:819–22.

[183] Monnet FP, Blier P, Debonnel G, de Montigny C. Modulation by

sigma ligands of N-methyl-D-aspartate-induced [3H]noradrenaline

release in the rat hippocampus: G-protein dependency. Naunyn-

Schmiedebergs Arch Pharmacol 1992;346:32–9.

[185] Monnet FP, Debonnel G, de Montigny C. In vivo electrophysiologi-

cal evidence for a selective modulation of N-methyl-D-aspartate-

induced neuronal activation in rat CA3 dorsal hippocampus by sigma

ligands. J Pharmacol Exp Ther 1992;261:123–30.

[186] Monnet FP, Debonnel G, Junien JL, De Montigny C. N-methyl-D-

aspartate-induced neuronal activation is selectively modulated by

sigma receptors. Eur J Pharmacol 1990;179:441–5.

[187] Monnet FP, Mahe V, Robel P, Baulieu EE. Neurosteroids, via sigma

receptors, modulate the [3H]norepinephrine release evoked by N-

methyl-D-aspartate in the rat hippocampus. Proc Natl Acad Sci USA

1995;92:3774–8.

[188] Morin-Surun MP, Collin T, Denavit-Saubie M, Baulieu EE, Monnet

FP. Intracellular s1 receptor modulates phospholipase C and protein

kinase C activation in the brain stem. Proc Natl Acad Sci USA 1999;

96:8196–9.

[189] Moriwaki A, Wang JB, Svingos A, van Bockstaele E, Cheng P,

Pickel V, Uhl GR. m Opiate receptor immunoreactivity in rat central

nervous system. Neurochem Res 1996;21:1315–31.

[190] Musacchio JM, Klein M, Santiago LJ. High affinity dextromethor-

phan binding sites in guinea pig brain: further characterization and

allosteric interactions. J Pharmacol Exp Ther 1988;247:424–31.

[191] Negus SS, Mello NK, Portoghese PS, Lin CE. Effects of kappa

opioids on cocaine self-administration by rhesus monkeys.

J Pharmacol Exp Ther 1997;282:44–55.

[192] Nestler EJ, Aghajanian GK. Molecular and cellular basis of

addiction. Science 1997;278:58–63.

[193] Nestler EJ. Molecular mechanisms of opiate and cocaine addiction.

Curr Opin Neurobiol 1997;7:713–9.

[194] Novakova M, Ela C, Barg J, Vogel Z, Hasin Y, Eilam Y. Inotropic

action of s receptor ligands in isolated cardiac myocytes from adult

rats. Eur J Pharmacol 1995;286:19–30.

[195] Novakova M, Ela C, Bowen WD, Hasin Y, Eilam Y. Highly

selective sigma receptor ligands elevate inositol 1,4,5-trisphosphate

production in rat cardiac myocytes. Eur J Pharmacol 1998;353:

315–27.

[196] O’Brien CP, Childress AR, Ehrman R, Robbins SJ. Conditioning

factors in drug abuse: can they explain compulsion?

J Psychopharmacol 1998;12:15–22.

[197] O’Brien CP, McLellan AT. Myths about the treatment of addiction.

Lancet 1996;347:237–40.

[198] Okuyama S, Chaki S, Yae T, Nakazato A, Muramatsu M.

Autoradiographic characterization of binding sites for [3H]NE-100

in guinea pig brain. Life Sci 1995;57:PL333–7.

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527524

[199] Okuyama S, Imagawa Y, Ogawa S, Araki H, Ajima A, Tanaka M,

Muramatsu M, Nakazato A, Yamaguchi K, Yoshida M. NE-100, a

novel sigma receptor ligand: in vivo tests. Life Sci 1993;53:

PL285–90.

[200] Okuyama S, Imagawa Y, Sakagawa T, Nakazato A, Yamaguchi K,

Katoh M, Yamada S, Araki H, Otomo S. NE-100, a novel sigma

receptor ligand: effect on phencyclidine-induced behaviors in rats,

dogs and monkeys. Life Sci 1994;55:PL133–8.

[201] Pan YX, Mei J, Xu J, Wan BL, Zuckerman A, Pasternak GW.

Cloning and characterization of a mouse s1 receptor. J Neurochem

1998;70:2279–85.

[202] Parsons LH, Koob GF, Weiss F. RU 24969, a 5-HT1B/1A receptor

agonist, potentiates cocaine-induced increases in nucleus accumbens

dopamine. Synapse 1999;32:132–5.

[203] Parsons LH, Weiss F, Koob GF. Serotonin1B receptor stimulation

enhances dopamine-mediated reinforcement. Psychopharmacology

1996;128:150–60.

[204] Parsons LH, Weiss F, Koob GF. Serotonin1B receptor stimulation

enhances cocaine reinforcement. J Neurosci 1998;18:10078–89.

[205] Partridge B, Schenk S. Context-independent sensitization to the

locomotor-activating effects of cocaine. Pharmacol Biochem Behav

1999;63:543–8.

[206] Patrick SL, Walker JM, Perkel JM, Lockwood M, Patrick RL.

Increases in rat striatal extracellular dopamine and vacuous chewing

produced by two sigma receptor ligands. Eur J Pharmacol 1993;231:

243–9.

[207] Phan VL, Alonso G, Sandillon F, Privat A, Maurice T. Therapeutic

potentials of sigma1 (s1) receptor ligands against cognitive deficits

in aging. Soc Neurosci Abstr 2000;26:2172.

[208] Piazza PV, Deminiere JM, le Moal M, Simon H. Stress- and

pharmacologically-induced behavioral sensitization increases vul-

nerability to acquisition of amphetamine self-administration. Brain

Res 1990;514:22–6.

[209] Pickens R, Thompson T. Cocaine-reinforced behavior in rats: effects

of reinforcement magnitude and fixed-ratio size. J Pharmacol Exp

Ther 1968;161:122–9.

[210] Pierce RC, Bell K, Duffy P, Kalivas PW. Repeated cocaine augments

excitatory amino acid transmission in the nucleus accumbens only in

rats having developed behavioral sensitization. J Neurosci 1996;6:

1550–60.

[211] Pilla M, Perachon S, Sautel F, Garrido F, Mann A, Wermuth CG,

Schwartz JC, Everitt BJ, Sokoloff P. Selective inhibition of cocaine-

seeking behaviour by a partial dopamine D3 receptor agonist. Nature

1999;400:371–5.

[212] Pionteck JA, Wang RY. Acute and subchronic effects of rimcazole

(BW 234U), a potential antipsychotic drug, on A9 and A10

dopamine neurons in the rat. Life Sci 1986;39:651–8.

[213] Poncelet M, Santucci V, Paul R, Gueudet C, Lavastre S, Guitard J,

Steinberg R, Terranova JP, Breliere JC, Soubrie P. Neuropharma-

cological profile of a novel and selective ligand of the sigma site: SR

31742A. Neuropharmacology 1993;32:605–15.

[214] Post RM, Kopanda RT, Black KE. Progressive effects of cocaine on

behavior and central amine metabolism in rhesus monkeys:

relationship to kindling and psychosis. Biol Psychiatry 1976;11:

403–19.

[215] Post RM, Lockfeld A, Squillace KM, Contel NR. Drug-environment

interaction: context dependency of cocaine-induced behavioral

sensitization. Life Sci 1981;28:755–60.

[216] Post RM. Intermittent versus continuous stimulation: effect of time

interval on the development of sensitization or tolerance. Life Sci

1980;26:1275–82.

[217] Prasad PD, Li HW, Fei YJ, Ganapathy ME, Fujita T, Plumley LH,

Yang-Feng TL, Leibach FH, Ganapathy V. Exon–intron structure,

analysis of promoter region, and chromosomal localization of the

human type 1 sigma receptor gene. J Neurochem 1998;70:443–51.

[218] Pulvirenti L, Balducci C, Piercy M, Koob GF. Characterization of

the effects of the partial dopamine agonist terguride oncocaine self-

administration in the rat. J Pharmacol Exp Ther 1998;286:1231–8.

[219] Quirion R, Bowen WD, Itzhak Y, Junien JL, Musacchio JM,

Rothman RB, Su TP, Tam SW, Taylor DP. A proposal for the

classification of sigma binding sites. Trends Pharmacol Sci 1992;13:

85–6.

[220] Quirion R, Chicheportiche R, Contreras PC, Johnson KM, Lodge D,

Tam SW, Woods JH, Zukin SR. Classification and nomenclature of

phencyclidine and sigma receptor sites. Trends Neurosci 1987;10:

444–6.

[221] Ramamoorthy JD, Ramamoorthy S, Mahesh VB, Leibach FH,

Ganapathy V. Cocaine-sensitive s-receptor and its interaction with

steroid hormones in the human placental syncytiotrophoblast and in

choriocarcinoma cells. Endocrinology 1995;136:924–32.

[222] Reid MS, Berger SP. Evidence for sensitization of cocaine-induced

nucleus accumbens glutamate release. Neuroreport 1996;7:1325–9.

[223] Reid MS, Hsu Jr. K, Berger SP. Cocaine and amphetamine

preferentially stimulate glutamate release in the limbic system:

studies on the involvement of dopamine. Synapse 1997;27:95–105.

[224] Reith MEA, Meisler BE, Sershen H, Lajtha A. Structural require-

ments for cocaine congeners to interact with dopamine and serotonin

uptake sites in mouse brain and to induce stereotyped behavior.

Biochem Pharmacol 1986;35:1123–9.

[225] Richardson NR, Roberts DC. Progressive ratio schedules in drug

self-administration studies in rats: a method to evaluate reinforcing

efficacy. J Neurosci Meth 1996;66:1–11.

[226] Richter RM, Weiss F. In vivo CRF release in rat amygdala is

increased during cocaine withdrawal in self-administering rats.

Synapse 1999;32:254–61.

[227] Ritz MC, George FR. Cocaine-induced seizures and lethality appear

to be associated with distinct central nervous system binding sites.

J Pharmacol Exp Ther 1993;264:1333–43.

[228] Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ. Cocaine receptors on

dopamine transporters are related to self-administration of cocaine.

Science 1987;237:1219–23.

[229] Rivier C, Vale W. Cocaine stimulates adrenocorticotropin (ACTH)

secretion through a corticotropin-releasing factor (CRF)-mediated

mechanism. Brain Res 1987;422:403–6.

[230] Roache JD, Grabowski J, Schmitz JM, Creson DL, Rhoades HM.

Laboratory measures of methylphenidate effects in cocaine-

dependent patients receiving treatment. J Clin Psychopharmacol

2000;20:61–8.

[231] Robbins SJ, Ehrman RN, Childress AR, O’Brien CP. Relationships

among physiological and self-report responses produced by cocaine-

related cues. Addict Behav 1997;22:157–67.

[232] Robinson TE, Berridge KC. The neural basis of drug craving: an

incentive-sensitization theory of addiction. Brain Res Rev 1993;18:

247–91.

[233] Rogers CA, Lemaire S. Characterization of (þ )-[3H]3-PPP and

[3H]TCP binding sites in membrane preparations of bovine adrenal

medulla. Prog Clin Biol Res 1990;328:133–6.

[234] Roman F, Pascaud X, Chomette G, Bueno L, Junien JL.

Autoradiographic localization of sigma opioid receptors in the

gastrointestinal tract of the guinea pig. Gastroenterology 1989;97:

76–82.

[235] Roman F, Pascaud X, Vauche D, Junien JL. Evidence for a non-

opioid sigma binding site in the guinea-pig myenteric plexus. Life

Sci 1988;42:2217–22.

[236] Romieu P, Martin-Fardon R, Maurice T. Involvement of the s1

receptor in the cocaine-induced conditioned place preference.

Neuroreport 2000;11:2885–8.

[237] Romieu P, Phan VL, Martin-Fardon R, Maurice T. The sigma1

receptor involvement in cocaine-induced conditioned place pre-

ference is consequent upon dopamine uptake blockade. Neuropsy-

chopharmacology 2002;26:444–55.

[238] Rothman RB, Glowa JR. A review of the effects of dopaminergic

agents on humans, animals, and drug-seeking behavior, and its

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527 525

implications for medication development. Focus on GBR 12909.

Mol Neurobiol 1995;11:1–19.

[239] Rothman RB. High affinity dopamine reuptake inhibitors as potential

cocaine antagonists: a strategy for drug development. Life Sci 1990;

46:PL17–PL21.

[240] Samovilova NN, Nagornaya LV, Vinogradov VA. (þ )-[3H]SK and

F 10,047 binding sites in rat liver. Eur J Pharmacol 1988;147:

259–64.

[241] Samovilova NN, Vinogradov VA. Subcellular distribution of (þ)-

[3H]SKF 10,047 binding sites in rat liver. Eur J Pharmacol 1992;225:

69–74.

[242] Sanchez-Arroyos R, Guitart X. Electrophysiological effects of E-

5842, a sigma1 receptor ligand and potential atypical antipsychotic,

on A9 and A10 dopamine neurons. Eur J Pharmacol 1999;378:31–7.

[243] Sarnyai Z, Biro E, Gardi J, Vecsernyes M, Julesz J, Telegdy G. Brain

corticotropin-releasing factor mediates anxiety-like behavior

induced by cocaine withdrawal in rats. Brain Res 1995;675:89–97.

[244] Sarnyai Z, Biro E, Penke B, Telegdy G. The cocaine-induced

elevation of plasma corticosterone is mediated by endogenous

corticotropin-releasing factor (CRF) in rats. Brain Res 1992;589:

154–6.

[245] Sarnyai Z, Shaham Y, Heinrichs SC. The role of corticotropin-

releasing factor in drug addiction. Pharmacol Rev 2001;53:209–43.

[246] Satel SL, Krystal JH, Delgado PL, Kosten TR, Charney DS.

Tryptophan depletion and attenuation of cue-induced craving for

cocaine. Am J Psychiatry 1995;152:778–83.

[247] Schechter MD, Calcagnetti DJ. Continued trends in the conditioned

place preference literature from 1992 to 1996, inclusive, with a

cross-indexed bibliography. Neurosci Biobehav Rev 1998;22:

827–46.

[248] Schechter MD, Calcagnetti DJ. Trends in place preference

conditioning with a cross-indexed bibliography; 1957–1991.

Neurosci Biobehav Rev 1993;17:21–41.

[249] Schenk S, Valadez A, Worley CM, McNamara C. Blockade of the

acquisition of cocaine self-administration by the NMDA antagonist

MK-801 (dizocilpine). Behav Pharmacol 1993;4:652–9.

[250] Self DW, Barnhart WJ, Lehman DA, Nestler EJ. Opposite

modulation of cocaine-seeking behavior by D1- and D2-like

dopamine receptor agonists. Science 1996;271:1586–9.

[251] Self DW, Nestler EJ. Relapse to drug seeking: neural and molecular

mechanisms. Drug Alcohol Depend 1998;51:49–60.

[252] Seth P, Fei YJ, Li HW, Huang W, Leibach FH, Ganapathy V.

Cloning and functional characterization of a sigma receptor from rat

brain. J Neurochem 1998;70:922–31.

[253] Seth P, Leibach FH, Ganapathy V. Cloning and structural analysis of

the cDNA and the gene encoding the murine type 1 sigma receptor.

Biochem Biophys Res Commun 1997;241:535–40.

[254] Sharkey J, Glen KA, Wolfe S, Kuhar MJ. Cocaine binding at s

receptors. Eur J Pharmacol 1988;149:171–4.

[255] Sivam SP. Cocaine selectively increases striatonigral dynorphin

levels by a dopaminergic mechanism. J Pharmacol Exp Ther 1989;

250:818–24.

[256] Skuza G, Golembiowska K, Wedzony K. Effect of EMD 57445, the

selective s receptor ligand, on the turnover and release of dopamine.

Pol J Pharmacol 1998;50:61–4.

[257] Skuza G. Effect of sigma ligands on the cocaine-induced convulsions

in mice. Pol J Pharmacol 1999;51:477–83.

[258] Smith JA, Mo Q, Guo H, Kunko PM, Robinson SE. Cocaine

increases extraneuronal levels of aspartate and glutamate in the

nucleus accumbens. Brain Res 1995;683:264–9.

[259] Soares-da-Silvia P, Garrett MC. A kinetic study of the rate of

formation of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC)

and homovanillic acid (HVA) in the brain of the rat: implications for

the origin of DOPAC. Neuropharmacology 1990;29:869–74.

[260] Sora I, Hall FS, Andrews AM, Itokawa M, Li XF, Wei HB, Wichems

C, Lesch KP, Murphy DL, Uhl GR. Molecular mechanisms of

cocaine reward: combined dopamine and serotonin transporter

knockouts eliminate cocaine place preference. Proc Natl Acad Sci

USA. 2001;98:5300–5.

[261] Sora I, Wichems C, Takahashi N, Li XF, Zeng Z, Revay R, Lesch

KP, Murphy DL, Uhl GR. Cocaine reward models: conditioned place

preference can be established in dopamine- and in serotonin-

transporter knockout mice. Proc Natl Acad Sci USA 1998;95:

7699–704.

[262] Spangler R, Ho A, Zhou Y, Maggos CE, Yuferov V, Kreek MJ.

Regulation of kappa opioid receptor mRNA in the rat brain by binge

pattern cocaine administration and correlation with preprodynorphin

mRNA. Brain Res Mol Brain Res 1996;38:71–6.

[263] Spangler R, Unterwald EM, Kreek M. Binge cocaine administration

induces a sustained increase of prodynorphin mRNA in rat caudate-

putamen. Brain Res Mol Brain Res 1993;19:323–7.

[264] Spealman RD, Barret-Larimore RL, Rowlett JK, Platt DM, Khroyan

TV. Pharmacological and environmental determinants of relapse to

cocaine-seeking behavior. Pharmacol Biochem Behav 1999;64:

327–36.

[265] Spealman RD. Modification of behavioral effects of cocaine by

selective serotonin and dopamine uptake inhibitors in squirrel

monkeys. Psychopharmacology 1993;112:93–9.

[266] Steinfels GF, Tam SW, Cook L. Electrophysiological effects of

selective sigma-receptor agonists, antagonists, and the selective

phencyclidine receptor agonist MK-801 on midbrain dopamine

neurons. Neuropsychopharmacology 1989;2:201–8.

[267] Steinfels GF, Tam SW. Selective sigma receptor agonist and

antagonist affect dopamine neuronal activity. Eur J Pharmacol 1989;

163:167–70.

[268] Stewart RB, Grabowski J, Wang NS, Meisch RA. Orally delivered

methadone as a reinforcer in rhesus monkeys. Psychopharmacology

1996;123:111–8.

[269] Stolerman I. Drugs of abuse: behavioural principles, methods and

terms. Trends Pharmacol Sci 1992;13:170–6.

[270] Su TP, Hayashi T. Cocaine affects the dynamics of cytoskeletal

proteins via sigma(1) receptors. Trends Pharmacol Sci 2001;22:

456–8.

[271] Su TP, Junien JL. Sigma receptors in the central nervous system and

the periphery. In: Itzhak Y, editor. Sigma receptors. San Diego:

Academic Press; 1994. p. 21–44.

[272] Su TP, Wu XZ. Guinea pig vas deferens contains sigma but not

phencyclidine receptors. Neurosci Lett 1990;108:341–5.

[273] Su TP. Evidence for sigma opioid receptor: binding of [3H]SKF-

10047 to etorphine-inaccessible sites in guinea-pig brain.

J Pharmacol Exp Ther 1982;223:284–90.

[274] Swanson CJ, Kalivas PW. Regulation of locomotor activity by

metabotropic glutamate receptors in the nucleus accumbens and

ventral tegmental area. J Pharmacol Exp Ther 2000;292:406–14.

[275] Szumlinski KK, Allan M, Talangbayan H, Tracey A, Szechtman H.

Locomotor sensitization to quinpirole: environment-modulated

increase in efficacy and context-dependent increase in potency.

Psychopharmacology 1997;134:193–200.

[276] Tallaksen-Greene SJ, Kaatz KW, Romano C, Albin RL. Localization

of mGluR1a-like immunoreactivity and mGluR5-like immunoreac-

tivity in identified populations of striatal neurons. Brain Res 1998;

780:210–7.

[277] Tam SW, Cook L. Sigma opiates and certain antipsychotic drugs

mutually inhibit (þ )-[3H] SKF 10,047 and [3H]haloperidol binding

in guinea pig brain membranes. Proc Natl Acad Sci USA 1984;81:

5618–21.

[278] Tatum AL, Seevers MH. Experimental cocaine addiction.

J Pharmacol Exp Ther 1929;36:401–10.

[279] Taylor DP, Dekleva J. Potential antipsychotic BMY-14,802

selectively binds to sigma sites. Drug Dev Res 1987;11:65–70.

[280] Taylor DP, Eison MS, Moon SL, Yocca FD. BMY-14,802: a

potential antipsychotic with selective affinity for s-binding sites.

Adv Neuropsychiatr Psychopharmacol 1991;1:307–15.

[281] Tolliver BK, Carney JM. Sensitization to stereotypy in DBA/2J but

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527526

not C57BL/6J mice with repeated cocaine. Pharmacol Biochem

Behav 1994;48:169–73.

[284] Ujike H, Kuroda S, Otsuki S. s Receptor antagonists block the

development of sensitization to cocaine. Eur J Pharmacol 1996;296:

123–8.

[285] Ujike H, Tsuchida K, Akiyama K, Otsuki S. Supersensitivity of s

receptors after repeated administration of cocaine. Life Sci 1992;51:

PL31–6.

[286] Ukai M, Mori E, Kameyama T. Modulatory effects of morphine, U-

50488H and 1,3-di-(2-tolyl)guanidine on cocaine-like discriminative

stimulus in the rat using two-choice discrete-trial avoidance

paradigm. Meth Find Exp Clin Pharmacol 1997;19:541–6.

[287] Undie AS, Berki AC, Beardsley K. Dopaminergic behaviors and

signal transduction mediated through adenylate and phospholipase C

pathways. Neuropharmacology 2000;39:75–87.

[288] Ungless MA, Whistler JL, Malenka RC, Bonci A. Single cocaine

exposure in vivo induces long-term potentiation in dopamine

neurons. Nature 2001;411:583–7.

[289] Unterwald EM, Rubenfeld JM, Kreek MJ. Repeated cocaine

administration upregulates kappa and mu, but not delta, opioid

receptors. Neuroreport 1994;5:1613–6.

[290] Urani A, Roman FJ, Phan VL, Su TP, Maurice T. The

antidepressant-like effect induced by sigma1-receptor agonists and

neuroactive steroids in mice submitted to the forced swimming test.

J Pharmacol Exp Ther 2001;298:1269–79.

[291] Vanderschuren LJ, Kalivas PW. Alterations in dopaminergic and

glutamatergic transmission in the induction and expression of

behavioral sensitization: a critical review of preclinical studies.

Psychopharmacology (Berl) 2000;151:99–120.

[292] Vaupel DB. Naltrexone fails to antagonize the sigma effects of PCP

and SKF-10,047 in the dog. Eur J Pharmacol 1983;92:269–74.

[293] Vezina P, Kim JH. Metabotropic glutamate receptors and the

generation of locomotor activity: interactions with midbrain

dopamine. Neurosci Biobehav Rev 1999;23:577–89.

[294] Vignon J, Pinet V, Cerruti C, Kamenka JM, Chicheportiche R.

[3H]N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine

([3H]BTCP): a new phencyclidine analog selective for the dopamine

uptake complex. Eur J Pharmacol 1988;148:427–36.

[296] Vincent SL, Khan Y, Benes FM. Cellular distribution of dopamine

D1 and D2 receptors in rat medial prefrontal cortex. J Neurosci 1993;

13:2551–64.

[297] Wachtel SR, White FJ. Electrophysiological effects of BMY 14,802,

a new potential antipsychotic drug, on midbrain dopamine neurons in

the rat: acute and chronic studies. J Pharmacol Exp Ther 1988;244:

410–6.

[298] Walker JM, Bowen WD, Walker FO, Matsumoto RR, De Costa B,

Rice KC. Sigma receptors: biology and function. Pharmacol Rev

1990;42:355–402.

[299] Wallace BC. Psychological and environmental determinants of

relapse in crack cocaine smokers. J Subst Abuse Treat 1989;6:

95–106.

[300] Walsh SL, Preston KL, Sullivan JT, Fromme R, Bigelow GE.

Fluoxetine alters the effects of intravenous cocaine in humans. J Clin

Psychopharmacol 1994;14:396–407.

[301] Wang HY, Undie AS, Friedman E. Evidence for the coupling of Gq

protein to D1-like dopamine sites in rat striatum: possible role in

dopamine-mediated inositol phosphate formation. Mol Pharmacol

1995;48:988–94.

[302] Warner EA. Cocaine abuse. Ann Int Med 1993;119:226–35.

[303] Weiner DM, Levey AI, Sunahara RK, Niznik HB, O’Dowd BF,

Seeman P, Brann MR. D1 and D2 dopamine receptor mRNA in rat

brain. Proc Natl Acad Sci USA 1991;88:1859–63.

[304] Weiser SD, Patrick SL, Mascarella SW, Downing-Park J, Bai X,

Carroll FI, Walker JM, Patrick RL. Stimulation of rat striatal tyrosine

hydroxylase activity following intranigral administration of sigma

receptor ligands. Eur J Pharmacol 1995;275:1–7.

[305] Weiss F, Maldonado-Vlaar CS, Parsons LH, Kerr TM, Smith DL,

Ben-Shahar O. Control of cocaine-seeking behavior by drug-

associated stimuli in rats: effects on recovery of extinguished

operant-responding and extracellular dopamine levels in amygdala

and nucleus accumbens. Proc Natl Acad Sci USA 2000;97:4321–6.

[306] Weiss F, Martin-Fardon R, Ciccociopppo R, Kerr TM, Smith DL,

Ben-Shahar O. Enduring resistance to extinction of cocaine-seeking

behavior induced by drug-related cues. Psychopharmacology 2001;

25:361–72.

[307] Weiss SR, Post RM, Pert A, Woodward R, Murman D. Context-

dependent cocaine sensitization: differential effect of haloperidol on

development versus expression. Pharmacol Biochem Behav 1989;

34:655–61.

[308] Werme M, Thoren P, Olson L, Brene S. Running and cocaine both

upregulate dynorphin mRNA in medial caudate putamen. Eur J

Neurosci 2000;12:2967–74.

[309] Werner TE, Smith SG, Davis WM. A dose-response comparison

between methadone and morphine self-administration. Psychophar-

macologia 1976;47:209–11.

[310] White FJ, Kalivas PW. Neuroadaptations involved in amphetamine

and cocaine addiction. Drug Alcohol Depend 1998;51:141–53.

[311] Wikler A. Dynamics of drug dependence. Implications of a

conditioning theory for research and treatment. Arch Gen Psychiatry

1973;28:611–6.

[312] Wise RA, Murray A, Bozarth MA. Bromocriptine self-adminis-

tration and bromocriptine-reinstatement of cocaine-trained and

heroin-trained lever pressing in rats. Psychopharmacology 1990;

100:355–60.

[313] Witkin JM, Terry M, Menkel M, Hickey P, Pontecorvo M, Ferkany J,

Katz JL. Effects of the selective sigma receptor ligand 6-[6-(4-

hydroxypiperidinyl)hexyloxy]-3-methylflavone (NPC 16377), on

behavioral and toxic effects of cocaine. J Pharmacol Exp Ther

1993;266:473–82.

[314] Wolf ME. The role of excitatory amino acids in behavioral sensitization

to psychomotor stimulants. Prog Neurobiol 1998;54:679–720.

[315] Wolfe SA, Culp SG, De Souza EB. Sigma-receptors in endocrine

organs: identification, characterization, and autoradiographic local-

ization in rat pituitary, adrenal, testis, and ovary. Endocrinology

1989;124:1160–72.

[316] Wolfe SA, Kulsakdinun C, Battaglia G, Jaffe JH, De Souza EB.

Initial identification and characterization of sigma receptors on

human peripheral blood leukocytes. J Pharmacol Exp Ther 1988;

247:1114–9.

[317] Woolverton WL, Johnson KM. Neurobiology of cocaine abuse.

Trends Pharmacol Sci 1992;13:193–200.

[318] Woolverton WL. Determinants of cocaine self-administration by

laboratory animals. Ciba Found Symp 1992;166:149–61.

[319] Yokel RA, Wise RA. Attenuation of intravenous amphetamine

reinforcement by central dopamine blockade in rats. Psychophar-

macology 1976;48:311–8.

[320] Yokel RA, Wise RA. Increased lever pressing for amphetamine after

pimozide in rats: implications for a dopamine theory of reward.

Science 1975;187:547–9.

[321] Zamanillo D, Andreu F, Ovalle S, Perez MP, Romero G, Farre AJ,

Guitart X. Up-regulation of sigma1 receptor mRNA in rat brain by a

putative atypical antipsychotic and sigma receptor ligand. Neurosci

Lett 2000;282:169–72.

[322] Zetterstrom T, Sharp T, Collin AK, Ungerstedt U. In vivo

measurement of extracellular dopamine and DOPAC in rat striatum

after various dopamine-releasing drugs; implications for the origin

of extracellular DOPAC. Eur J Pharmacol 1988;148:327–34.

[323] Zhang JZ, Chiodo LA, Freeman AS. Further characterization of the

effects of BMY-14,802 on dopamine neuronal activity. Synapse

1993;15:276–84.

[324] Zhang JZ, Chiodo LA, Wettstein JG, Junien JL, Freeman AS. Acute

effects of sigma ligands on the electrophysiological activity of rat

nigrostriatal and mesoaccumbal dopaminergic neurons. Synapse

1992;11:267–78.

T. Maurice et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 499–527 527