Mechanisms underlying the psychiatric effects of IFN- α , particularly in anhedonia

1. 07/22/08 Mechanisms underlying the psychiatric effects of IFN-α, particularly in anhedonia Edith Grosbellet M1 Signalisation cellulaire et Neurosciences Paris XI/ENS de Cachan

2. Type I Type II γ α β Leukocytes Fibroblastes Activated T-cells NK Generalities about IFNs Interferons Antiviral activities Inhibition of cell growth Control of apoptosis 3 types of IFN:

3. 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

4. Psychiatric symptoms reportedly associated with IFN-α treatment Mild depression Anxiety Memory loss Amotivation Generalised cognitive slowing Severe depression Suicidal ideation or manic/paranoid psychoses

5. Anhedonia Water Water + Sugar Depressive disorders Floating time in the forced swim test As far as rats are concerned…. Intracisternal administration of human IFN-α , 5 min before the test Makino et al, 2000 n=10

6. What mechanisms are underlying IFN-a’s psychiatric adverse effects, particularly anhedonia?

7. CONTENTS • Introduction • The reward pathway • 2. IFN-α and Dopamine • 3. IFN-α and other neurotransmitters • Discussion/Perspectives

8. The reward pathway Role for DA in depressive disorders (Hamner and Diamon, 1996)

9. The reward pathway Nigrostriatal Delicate DA balance Substantia nigra Striatum Cortex areas (PFC) VTA NAcc Mesolimbic/mesocortical Modified from Hyman et al (2006)

10. Single i.c.v. injection DA levels increased in striatum (Kamata et al, 2000) IFN-α is much more highly active than both morphine and β-endorphins Molecular Basis Behaviour DA and IFN-α IFN-α has structural and antigenic relatedness to ACTH ( adrenocorticotrophic hormone) and endorphins (Blalock and Smith, 1980) Analgesic properties of IFN-α

11. DA 1000 700 Saline IFN-α 400 0 45 90 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 n=7 n=6 Brain levels (ng/g) Time after treatment (min) α -MT-induced depletion is decreased by repeated IFN- α administration DA neural activity in whole mouse brain homogenates

12. IFN-α can act like EOP N-term: Tyr-X-X-Phe IFN-α can actvia the μ-opioid receptors Anhedonia? Activity of IFN-α NAcc VTA Desensitization  Decrease of DA effects DA release GABA Dynorphine release

13. IFN-α and others neurotransmitters NA levels decreased in the PFC Single i.c.v. administration of humanIFN-α in rats NA levels increased in the striatum and hypothalamus Kamata et al, 2000 May be related to IFN-α induced fatigue in humans Levels of 5-HT significantly reduced in the prefrontal cortex, striatum, hypothalamus and midbrain Single i.c.v. administration of human IFN-α in rats Kamata et al, 2000 Levels of 5-HIAA reduced in striatum and midbrain Overall decrease in 5-HT activity

14. 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 Decreased cell proliferation caused by IFN-α –induced IL-1β may be responsible, at least in part, for IFN-α-induced depression Administration of IFN-α for 1 week (5000, 20000 or 50000 IU/kg/day, intravenously)

15. Thank you for your attention!

16. Appendix

19. 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