Citation

Maurice-Gélinas C, Deslauriers J, Monpays C, Sarret P, Grignon S. Physiol. Behav. 2018; 191: 65-72.

Affiliation

Departement of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 12e avenue Nord, Sherbrooke, QC J1H 5N4, Canada; Department of Psychiatry, Centre Hospitalier Universitaire de Sherbrooke, 580 Bowen Sud, Sherbrooke, QC J1G 2E8, Canada. Electronic address: Sylvain.Grignon@USherbrooke.ca.

Copyright

(Copyright © 2018, Elsevier Publishing)

DOI

10.1016/j.physbeh.2018.03.036

PMID

29630964

Abstract

Death by suicide is 5 times higher among schizophrenia patients than in the general population. There is now compelling evidence suggesting that the pathophysiology of suicide in schizophrenia does not involve central serotonergic neurotransmission disturbances, as has been shown in other contexts. We recently developed and characterized a murine Two-Hit Model of Suicide-related behavior in a schizophrenia-like context (THMS) (gestational inflammation with polyI:C at gestational day 12 followed by post-weaning social isolation). In this THMS model, we have recently shown that the atypical antipsychotic clozapine normalized the prepulse inhibition (PPI) deficits as well suicide-related, impulsive aggressive and anxiety-like behaviors. While the mechanisms underlying the suicide-reducing benefits of clozapine in schizophrenic patients are not well understood, previous works have revealed that clozapine alters brain levels of neurosteroids, such as allopregnanolone. In the present study, we thus investigated the role of endogenous neurosteroids in clozapine action by evaluating whether the 5α-reductase inhibitor finasteride could overturn the ability of clozapine to reduce suicide-related behaviors. We found that clozapine significantly improved the PPI deficits in THMS mice, which could not be reversed by finasteride treatment. However, finasteride counteracted the ability of clozapine to decrease the exploratory behaviors in the open-field test. In the resident-intruder test, THMS mice showed exacerbated aggressiveness and impulsivity following finasteride alone. In this resident-intruder paradigm, clozapine alone effectively blocked the finasteride-enhanced effects on aggression and impulsivity. Altogether, these findings support the existence of a complex interaction between clozapine and neurosteroids in THMS mice. Further investigations are now required to clarify the details of the molecular mechanisms involved.

Copyright © 2018. Published by Elsevier Inc.

Language: en

Keywords

Clozapine; Finasteride; Schizophrenia; Social isolation; Suicide; polyI:C