Budry Lionel, Bouyakdan Khalil, Tobin Stephanie, Rodaros Demetra, Marcher Ann-Britt, Mandrup Susanne, Fulton Stephanie, Alquier Thierry
Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal (CRCHUM), University of Montreal, Montreal, QC, H3T 1J4, Canada; Department of Medicine, University of Montreal, Montreal, QC, H3T 1J4, Canada.
Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal (CRCHUM), University of Montreal, Montreal, QC, H3T 1J4, Canada; Department of Biochemistry, University of Montreal, Montreal, QC, H3T 1J4, Canada.
Behav Brain Res. 2016 Oct 15;313:201-207. doi: 10.1016/j.bbr.2016.06.052. Epub 2016 Jun 27.
Diazepam is well known for its anxiolytic properties, which are mediated via activation of the GABAA receptor. Diazepam Binding Inhibitor (DBI), also called acyl-CoA binding protein (ACBP), is a ubiquitously expressed protein originally identified based on its ability to displace diazepam from its binding site on the GABAA receptor. Central administration of ACBP or its cleaved fragment, commonly referred to as endozepines, induces proconflict and anxiety-like behaviour in rodents. For this reason, ACBP is known as an anxiogenic peptide. However, the role of endogenous ACBP in anxiety-like behaviour and anxiolytic responses to diazepam has not been investigated. To address this question, we assessed anxiety behaviour and anxiolytic responses to diazepam in two complementary loss-of-function mouse models including astrocyte-specific ACBP KO (ACBP(GFAP) KO) and whole-body KO (ACBP KO) mice. Male and female ACBP(GFAP) KO and ACBP KO mice do not show significant changes in anxiety-like behaviour compared to control littermates during elevated plus maze (EPM) and open field (OF) tests. Surprisingly, ACBP(GFAP) KO and ACBP KO mice were unresponsive to the anxiolytic effect of a low dose of diazepam during EPM tests. In conclusion, our experiments using genetic ACBP loss-of-function models suggest that endozepines deficiency does not affect anxiety-like behaviour in mice and impairs the anxiolytic action of diazepam.
地西泮因其抗焦虑特性而广为人知，其抗焦虑作用是通过激活GABAA受体介导的。地西泮结合抑制剂（DBI），也称为酰基辅酶A结合蛋白（ACBP），是一种广泛表达的蛋白质，最初是根据其将地西泮从GABAA受体上的结合位点置换下来的能力而被鉴定出来的。在啮齿动物中，中枢给予ACBP或其裂解片段（通常称为内源性苯二氮䓬）会诱发冲突行为和焦虑样行为。因此，ACBP被称为一种致焦虑肽。然而，内源性ACBP在焦虑样行为和对地西泮的抗焦虑反应中的作用尚未得到研究。为了解决这个问题，我们在两种互补的功能缺失小鼠模型中评估了焦虑行为和对地西泮的抗焦虑反应，这两种模型包括星形胶质细胞特异性ACBP基因敲除（ACBP(GFAP) KO）小鼠和全身基因敲除（ACBP KO）小鼠。在高架十字迷宫（EPM）和旷场（OF）试验中，与对照同窝小鼠相比，雄性和雌性ACBP(GFAP) KO和ACBP KO小鼠的焦虑样行为没有显著变化。令人惊讶的是，在EPM试验中，ACBP(GFAP) KO和ACBP KO小鼠对低剂量地西泮的抗焦虑作用没有反应。总之，我们使用ACBP基因功能缺失模型进行的实验表明，内源性苯二氮䓬缺乏不会影响小鼠的焦虑样行为，但会削弱地西泮的抗焦虑作用。
