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 IType II LeukocytesFibroblastesActivated T-cells NK Interferons Antiviral activitiesInhibition of cell growthControl 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 Anxiety Memory 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…. AnhedoniaWater 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 Nigrostriatal The 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 DA Saline IFN-α α -MT-induced depletion is decreased by repeated IFN- α administration n=6 n=7 Time after treatment (min) Brain levels (ng/g)

Activity of IFN-α IFN-α can act like EOP N-term: Tyr-X-X-Phe IFN-α can act via the μ-opioid receptors NAcc VTA 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 midbrain Overall 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 week Decreased cell proliferation caused by IFN-α –induced IL-1β may be responsible, at least in part, for IFN-α- induced depression (5000, or IU/kg/day, intravenously)

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Appendix

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