Ford Matthew M, Beckley Ethan H, Nickel Jeffrey D, Eddy Sarah, Finn Deborah A
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239-3098, USA.
Drug Alcohol Depend. 2008 Sep 1;97(1-2):73-85. doi: 10.1016/j.drugalcdep.2008.03.021. Epub 2008 May 16.
The neurosteroid allopregnanolone (ALLO) is a positive modulator of GABA(A) receptors that exhibits a psychopharmacological profile similar to ethanol (i.e., anxiolytic, sedative-hypnotic). Based on research suggesting that manipulation of ALLO levels altered ethanol self-administration in male rodents, the current studies determined whether exogenous ALLO administration or the inhibition of its synthesis in vivo modulated ethanol intake patterns in female C57BL/6J mice. Lickometer circuits collected temporal lick records of ethanol (10%, v/v) and water consumption during daily 2h limited access sessions. Following the establishment of stable ethanol intake, studies examined the effect of an acute ALLO challenge (3.2-24.0 mg/kg) or a 7-day blockade of ALLO production with finasteride (FIN; 50 or 100 mg/kg) on ethanol intake in a within-subjects design. In contrast to results in male mice, ethanol dose (g/kg), ethanol preference and most of the bout parameters were unaltered by ALLO pretreatment in female mice. Ethanol intake in females also was recalcitrant to 7-day treatment with 50 mg/kg FIN, whereas 100 mg/kg FIN significantly reduced the ethanol dose consumed by 35%. The FIN-attenuated ethanol intake was attributable to a significant decrease in bout frequency (up to 45%), with lick patterns indicating reduced maintenance of consumption throughout the 2-h session. FIN also produced a dose-dependent decrease in brain ALLO levels. In conjunction with data in male mice, the present findings indicate that there are sex differences in the physiological regulation of ethanol intake patterns by GABAergic neurosteroids.
神经甾体别孕烷醇酮（ALLO）是GABA(A)受体的正向调节剂，其表现出与乙醇相似的精神药理学特征（即抗焦虑、镇静催眠）。基于研究表明，对雄性啮齿动物体内ALLO水平的操控会改变乙醇自我给药行为，当前的研究确定了外源性给予ALLO或体内抑制其合成是否会调节雌性C57BL/6J小鼠的乙醇摄入模式。舔舐计数器电路收集了在每日2小时有限获取时段内乙醇（10%，v/v）和水消耗的时间舔舐记录。在稳定的乙醇摄入量确立后，研究采用受试者内设计，检测了急性ALLO激发（3.2 - 24.0 mg/kg）或用非那雄胺（FIN；50或100 mg/kg）进行7天的ALLO生成阻断对乙醇摄入的影响。与雄性小鼠的结果相反，雌性小鼠中乙醇剂量（g/kg）、乙醇偏好以及大多数发作参数在ALLO预处理后未发生改变。雌性小鼠的乙醇摄入量对50 mg/kg FIN的7天治疗也不敏感，而100 mg/kg FIN显著降低了35%的乙醇消耗量。FIN使乙醇摄入量减少归因于发作频率显著降低（高达45%），舔舐模式表明在整个2小时时段内维持消耗的能力下降。FIN还使脑内ALLO水平呈剂量依赖性降低。结合雄性小鼠的数据，目前的研究结果表明，GABA能神经甾体对乙醇摄入模式的生理调节存在性别差异。
