Mechanisms underlying the psychiatric effects of

IFN-α, particularly in anhedonia

Edith Grosbellet

M1 Signalisation cellulaire et Neurosciences

Paris XI/ENS de Cachan

07/22/08

Generalities about IFNs

3 types of IFN:

α β γ

Type I Type II

Leukocytes Fibroblastes Activated T-cells

NK

Interferons

Antiviral activities Inhibition of cell growth Control of apoptosis

Generalities about IFN-α

IFN- α :

First cytokine to be produced by recombinant DNA technology (1981)

Antiviral and antiproliferative properties

Signalisation via a STAT/Jak pathway

Key treatment for HCV (Hepatitis C)

But a lot of adverse effects…

General medical symptoms

Flu-like

Gastrointestinal

Haematologic

Dermatologic

Respiratory…

Wide range of psychiatric disturbances

Mild depression

AnxietyMemory loss

Amotivation

Generalised cognitive slowing

Severe depression

Suicidal ideation or manic/paranoid psychoses

Psychiatric symptoms reportedly associated with IFN-α treatment

As far as rats are concerned….

• Anhedonia

Water

Water + Sugar

Depressive disorders•

Floating time in the forced swim test

Intracisternal administration of human IFN-α , 5 min before the test

Makino et al, 2000

n=10

What mechanisms are underlying IFN-a’s psychiatric adverse effects, particularly

anhedonia?

CONTENTS

Introduction

1. The reward pathway

2. IFN-α and Dopamine

3. IFN-α and other neurotransmitters

Discussion/Perspectives

The reward pathway

Role for DA in depressive disorders (Hamner and Diamon, 1996)

NAcc

Striatum

VTA

Cortex areas

(PFC)

Mesolimbic/mesocortical

NigrostriatalThe reward pathway

Modified from Hyman et al (2006)

Delicate DA balance

Substantia nigra

DA and IFN-α

• IFN-α has structural and antigenic relatedness to ACTH ( adrenocorticotrophic hormone) and endorphins (Blalock and Smith, 1980)

• IFN-α is much more highly active than both morphine and β-endorphins

BehaviourMolecular Basis

Analgesic properties of IFN-α

DA levels increased in striatum•

Single i.c.v. injection

(Kamata et al, 2000)

DA and IFN-α

• IFN-α can act like an EOP Dishinibit DAergic neurons in the VTA

• However, long-term opiate abuse may down-regulate dopaminergic tone

Shuto et al (1997)Repeated (once a day for 5 days), systemic, high-dose IFN-α administration

DA neural activity in whole mouse brain homogenates

1000

700

400

450 90

DA

Saline

IFN-α

α -MT-induced depletion is decreased by repeated IFN- α administration

n=6

n=7

Time after treatment (min)

Bra

in le

vels

(ng

/g)

Activity of IFN-α

IFN-α can act like EOP

N-term: Tyr-X-X-PheIFN-α can act via the μ-opioid receptors

NAccVTA

GABA

DA release

Dynorphine release

Desensitization

Decrease of DA effects

Anhedonia?

IFN-α and others neurotransmitters

Single i.c.v. administration of human IFN-α in rats

NA levels decreased in the PFC

NA levels increased in the striatum and hypothalamus

•

Kamata et al, 2000

May be related to IFN-α induced fatigue in humans

Single i.c.v. administration of human IFN-α in rats

•

Levels of 5-HT significantly reduced in the prefrontal cortex, striatum, hypothalamus and midbrain

Levels of 5-HIAA reduced in striatum and midbrainOverall decrease in 5-HT activity

Kamata et al, 2000

Discussion / Perspectives

• IFN-α acts like EOP’s, via μ-opioid receptors

• Effects of IFN-α on the reward pathway : interaction with DA, NA and 5-HT pathway

• Chronic treatment of high-dose IFN-α reduces DA neural activity

In the nigrostriatal system : Parkinson’s disease

In the mesolimbic/mesocortical system : Could explain many psychiatric effects, notably anhedonia, depressive disorders and associated anxiety

• IFN-α and neurogenesis?

Suppression of cell proliferation by Interferon-α through Interleukin-1 production in adult rat dentate gyrus, Kaneko et al, 2006

Administration of IFN-α for 1 weekDecreased cell proliferation caused by IFN-α –induced IL-1β may be responsible, at least in part, for IFN-α-induced depression

(5000, 20000 or 50000 IU/kg/day, intravenously)

Thank you for your attention!

Appendix

http://upload.wikimedia.org/wikipedia/commons/3/36/Gray768.png

http://upload.wikimedia.org/wikipedia/commons/7/7f/Neuronal_connections_of_nucleus_accumbens.JPEG

Activity of IFN-α

μ-opioid receptors are abundant in the Hippocampus

Six days of morphine treatment resulted in a significant reduction in levels of extracellular glutamate in mouse hippocampus

Decrease of cell proliferation in the sub-granular layer of the hippocampus

Modulation of the stability of dendritic spines?

Important role for EOP’s in the regulation of synaptic transmission and spine integrity