The 5α-reductase inhibitor finasteride increases suicide-related aggressive behaviors and blocks clozapine-induced beneficial effects in an animal model of schizophrenia.

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.

Mitochondrial Dysfunction in Schizophrenia: Determination of Mitochondrial Respiratory Activity in a Two-Hit Mouse Model.

Schizophrenia is a chronic mental illness in which mitochondrial dysfunction has been suggested. Our laboratory recently developed a juvenile murine two-hit model (THM) of schizophrenia based on the combination of gestational inflammation, followed by juvenile restraint stress. We previously reported that relevant behaviors and neurochemical disturbances, including oxidative stress, were reversed by the antioxidant lipoic acid (LA), thereby pointing to the central role played by oxidative abnormalities and prompting us to investigate mitochondrial function. Mitochondrial activity was determined with the MitoXpress® commercial kit in two schizophrenia-relevant regions (prefrontal cortex (PFC) and striatum). Measurements were performed in state 3, with substrates for complex I- and complex II-induced respiratory activity (IRA). We observed an increase in complex I IRA in the PFC and striatum in both sexes but an increase in complex II activity only in males. LA treatment prevented this increase only in complex II IRA in males. Expression levels of the different respiratory chain complexes, as well as fission/fusion proteins and protein carbonylation, were unchanged. In conclusion, our juvenile schizophrenia THM shows an increase in mitochondrial activity reversed by LA, specifically in complex II IRA in males. Further investigations are required to determine the mechanisms of these modifications.