Post on 02-Jul-2016
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