Sex differences in the effect of finasteride on acute ethanol withdrawal severity in C57BL/6J and DBA/2J mice
Sex differences in the effect of finasteride on acute ethanol withdrawal severity in C57BL/6J and DBA/2J mice
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DOI：
10.1016/j.neuroscience.2007.02.051
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发表时间：
2007-05-25
期刊：
影响因子：
3.3
通讯作者：
Finn, D. A.
中科院分区：
文献类型：
--
作者：
Gorin-Meyer, R. E.;Wiren, K. M.;Finn, D. A.
神经甾体别孕烯醇酮（allopregnanolone，ALLO）是GABA（A）受体的有效正调节剂，可调节乙醇（EtOH）戒断。5 α-还原酶抑制剂非那肽可以阻断ALLO和其他GABA能神经类固醇的形成，也可以降低EtOH的某些作用。在慢性EtOH暴露期间用非那肽治疗降低了EtOH戒断严重程度和血液EtOH浓度（BEC），表明非那肽对EtOH药代动力学的额外影响。因此，本研究的目的是确定非那肽对急性EtOH戒断严重程度的影响，以尽量减少非那肽对EtOH代谢的影响。雄性和雌性C57 BL/6 J和DBA/2 J小鼠接受非那肽（50 mg/kg i. p.）或媒介物24小时，然后注射EtOH（4g/kg i. p.）或盐水。在基线时对处理诱导的惊厥（HIC）进行评分，然后在注射EtOH或生理盐水后24小时内进行评分。在另一项实验中，在选定的时间点（0、2、8和24 h）评估血浆雌二醇和皮质酮水平。在最后一项研究中，在EtOH给药后30、60、120和240 min采集眶后血样，以评估芬那肽对EtOH清除参数的影响。预处理与finespide增加急性乙醇戒断严重程度的雌性C57 BL/6 J和DBA/2 J小鼠，但减少戒断严重程度的雄性小鼠的两个品系。芬必得没有改变BEC、EtOH清除率、雌二醇或皮质酮浓度，其方式似乎有助于芬必得对急性EtOH戒断严重程度影响的性别差异。这些发现表明，雄性和雌性C57 BL/6 J和DBA/2 J小鼠在急性乙醇戒断期间对ALLO或其他GABA能神经类固醇水平变化的敏感性不同。性别差异的GABA能5 α-还原类固醇的调制可能是一个重要的考虑因素，在理解和开发治疗干预酗酒。(c)2007年IBRO。由爱思唯尔有限公司出版。保留所有权利。
The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of GABA(A) receptors that can modulate ethanol (EtOH) withdrawal. The 5 alpha-reductase inhibitor finasteride can block the formation of ALLO and other GABAergic neurosteroids and also reduce certain effects of EtOH. Treatment with finasteride during chronic EtOH exposure decreased EtOH withdrawal severity and blood EtOH concentrations (BECs), suggesting an additional effect of finasteride on EtOH pharmacokinetics. Thus, the purpose of the present study was to determine the effect of finasteride on acute EtOH withdrawal severity, to minimize the effect of finasteride on EtOH metabolism. Male and female C57BL/6J and DBA/2J mice received a pretreatment of finasteride (50 mg/kg i.p.) or vehicle 24 h prior to an injection of EtOH (4 g/kg i.p.) or saline. Handling-induced convulsions (HICs) were scored at baseline, and then over a 24 h period after EtOH or saline injection. In another experiment, plasma estradiol and corticosterone levels were assessed at selected time points (0, 2, 8, and 24 h). In a final study, retro-orbital blood samples were collected at 30, 60, 120, and 240 min post-EtOH administration to access finasteride's effects on EtOH clearance parameters. Pretreatment with finasteride increased acute EtOH withdrawal severity in female C57BL/6J and DBA/2J mice but decreased withdrawal severity in male mice of both strains. Finasteride did not alter BECs, EtOH clearance, estradiol, or corticosterone concentrations in a manner that appeared to contribute to the sex difference in finasteride's effect on acute EtOH withdrawal severity. These findings suggest that male and female C57BL/6J and DBA/2J mice differ in their sensitivity to changes in ALLO or other GABAergic neurosteroid levels during acute EtOH withdrawal. Sex differences in the modulation of GABAergic 5 alpha-reduced steroids may be an important consideration in understanding and developing therapeutic interventions in alcoholics. (c) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.