Maurice-Gélinas Caroline, Deslauriers Jessica, Monpays Cécile, Sarret Philippe, Grignon Sylvain
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, University of California San Diego, La Jolla, CA, United States; Center of Excellence for Stress and Mental Health, Veterans Affairs Hospital, La Jolla, CA, United States.
Physiol Behav. 2018 Jul 1;191:65-72. doi: 10.1016/j.physbeh.2018.03.036. Epub 2018 Apr 7.
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.
精神分裂症患者的自杀死亡率比普通人群高5倍。目前有确凿证据表明，精神分裂症患者自杀的病理生理学并不涉及中枢5-羟色胺能神经传递障碍，这一点在其他情况下已得到证实。我们最近开发并描述了一种在精神分裂症样背景下与自杀相关行为的小鼠双打击模型（THMS）（在妊娠第12天用聚肌胞苷酸进行妊娠炎症，随后在断奶后进行社会隔离）。在这个THMS模型中，我们最近发现非典型抗精神病药物氯氮平可使前脉冲抑制（PPI）缺陷以及与自杀相关的、冲动攻击性和焦虑样行为恢复正常。虽然氯氮平对精神分裂症患者自杀减少益处的潜在机制尚不清楚，但先前的研究表明氯氮平会改变神经甾体的脑内水平，如别孕烯醇酮。因此，在本研究中，我们通过评估5α-还原酶抑制剂非那雄胺是否能推翻氯氮平减少自杀相关行为的能力，来研究内源性神经甾体在氯氮平作用中的作用。我们发现氯氮平显著改善了THMS小鼠的PPI缺陷，而非那雄胺治疗无法逆转这一效果。然而，非那雄胺抵消了氯氮平在旷场试验中减少探索行为的能力。在定居者-入侵者试验中，单独使用非那雄胺后，THMS小鼠表现出更强的攻击性和冲动性。在这个定居者-入侵者范式中，单独使用氯氮平有效地阻断了非那雄胺对攻击性和冲动性的增强作用。总之，这些发现支持了在THMS小鼠中氯氮平和神经甾体之间存在复杂相互作用。现在需要进一步研究以阐明所涉及分子机制的细节。
