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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
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)
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