La clozapine et les neurostéroïdes dans la modulation de comportements associés au suicide dans un modèle murin de schizophrénie

Suicide in schizophrenia is 5 times higher than in the general population. Compelling evidence now suggest that suicide in schizophrenia does not involve serotonin neurotransmission, at odds with general population. We recently described and characterized a murine Two-Hit Model of Suicide-related behavior in a schizophrenia-like context (THMS) (gestational inflammation followed by adolescent social isolation). In this model, clozapine normalized prepulse inhibition, aggressiveness, impulsivity and anxietylike behaviours in THMS mice. While the basis of clozapine superior effectiveness on suicidal behaviors in schizophrenic patients is not well understood, previous works has revealed that clozapine alters central neurosteroid (NS) levels, such as allopregnanolone. The present work was to evaluate if the effectiveness of clozapine for reducing the risk of recurrent suicidal behaviors is mediated through NS modulation. Finasteride, a 5α- reductase inhibitor was injected alone or before clozapine treatment in controls (ctl) and THMS mice. Prepulse inhibition (PPI), resident intruder test (RI) and exploratory behaviors (EB) were performed to assess the sensorimotor gating, aggressiveness/impulsivity and anxiety-like responses, respectively. Results showed that (1) PPI deficits in THMS mice are normalized by clozapine treatment (2) Finasteride administration to THMS mice elicited worsen aggressive behaviors in RI and clozapine eliminates these aggressive behaviors in THMS mice. However, finasteride did not reverse clozapine anti-aggressive effects. (3) Clozapine elicited sedation-like effect on locomotor activities in THMS mice, that was reversed by finasteride. These results suggest that the effects of clozapine on locomotor activity may be mediated following NS modulation and that the aggressive behaviors observed in THMS mice may be related to a down-regulation of NS. Analyzis of GABAA receptor subunits and 5αR subunits reveal no change between groups. Further experiments will be required to understand the seemingly contradictory results of CE and RI, but we demonstrate for the first time in a model that it is possible for clz to have an effect by NS modulation. Further research is needed to clarify if the antiaggressive effects of clozapine are mediated by NS modulation but we demonstrated for the first time in a sthat NS modulation is possible.

Name thesis:degree_name

M. Sc.

Level thesis:degree_level

Maîtrise

Discipline thesis:degree_discipline

Psychiatrie

Grantor dc:publisher

Université de Sherbrooke

Year dc:date.issued

2017

Author dc:creator

• Maurice-Gélinas, Caroline

Advisors dc:contributor.advisor

• Grignon, Sylvain
• Sarret, Philippe

• Schizophrénie
• Suicide
• Agressivité
• Clozapine
• Finastéride
• Neurostéroïdes
• Polyl:C
• Isolement social

Language dc:language.iso

fr, en

Handle dc:identifier.uri

http://hdl.handle.net/11143/11958

OAI identifier oai:identifier

oai:usherbrooke.scholaris.ca:11143/11958