Inhibition of 5α-reduced steroid biosynthesis impedes acquisition of ethanol drinking in male C57BL/6J mice
Inhibition of 5α-reduced steroid biosynthesis impedes acquisition of ethanol drinking in male C57BL/6J mice
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DOI：
10.1111/j.1530-0277.2008.00718.x
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发表时间：
2008-08-01
影响因子：
3.2
通讯作者：
Finn, Deborah A.
中科院分区：
文献类型：
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作者：
Ford, Matthew M.;Yoneyama, Naomi;Finn, Deborah A.
背景：Allopregnanolone (ALLO) 是一种生理相关的 GABA(A) 受体神经类固醇调节剂。它表现出的精神药理学特征与乙醇的摄入后效应非常相似。 5α-还原酶抑制剂非那雄胺（FIN）可抑制 ALLO 和结构相关神经类固醇的生物合成，先前已被证明可以减少有限乙醇消耗的维持。当前工作的主要目的是确定 FIN 是否会减少未接触过乙醇的小鼠的饮水行为。方法：使雄性 C57BL/6J (136) 小鼠适应反向光/暗时间表，并随意获取食物和水。在仅饮水前22小时习惯媒介物注射（VEH；20% w/v β-环糊精；腹腔注射）后，小鼠被分为3个治疗组：媒介物对照（VEH）、50 mg/kg FIN（FIN-50）。和 100 毫克/千克 FIN (FIN-100)。第一次治疗后二十二小时。小鼠首次被允许在 2 小时内有限地接触 10% v/v 乙醇溶液 (10E) 和水。在 FIN 治疗（7 天）和随后的 FIN 停药（13 天）阶段评估了 10E 摄入量和潜在饮酒模式。结果：FIN 剂量依赖性地阻止了 10E 饮酒的获得并阻止了乙醇偏好的发展，从而表明 GABA 能神经类固醇在建立稳定的饮酒模式中可能很重要。 FIN 引起的 10E 摄入量减少主要归因于发作频率的选择性和显着减少。因为 FIN 处理后没有观察到大小、持续时间或舔率的变化。尽管大脑 ALLO 水平完全恢复，但接受 FIN 治疗的小鼠在治疗后 2 周后继续表现出乙醇消耗量减少。第二项研究证实，每天注射 7 次 FIN 后，乙醇摄入量会向右和向下变化。饮用乙醇第七天后，大脑 ALLO 水平没有显着的组间差异。 FIN-50组的ALLO水平降低了28%。结论：虽然具体机制尚不清楚。 FIN 和其他调节 GABA 能系统的药理学干预措施可能有助于抑制高危个体的乙醇摄入量。
Background: Allopregnanolone (ALLO) is a physiologically relevant neurosteroid modulator of GABA(A) receptors. and it exhibits a psychopharmacological profile that closely resembles the post-ingestive effects of ethanol. The 5 alpha-reductase inhibitor finasteride (FIN), which inhibits biosynthesis of ALLO and structurally related neurosteroids, was previously demonstrated to reduce the maintenance of limited-access ethanol consumption. The primary aim of the current work was to determine whether FIN would reduce the acquisition of drinking in ethanol-naive mice.Methods: Male C57BL/6J (136) mice were acclimated to a reverse light/dark schedule, and were provided ad libitum access to chow and water. Following habituation to vehicle injections (VEH; 20% w/v beta-cyclodextrin; i.p.) administered 22-hour prior to drinking sessions with water only, mice were divided into 3 treatment groups: vehicle control (VEH), 50 mg/kg FIN (FIN-50). and 100 mg/kg FIN (FIN-100). Twenty-two hours after the first treatment. mice were permitted the inaugural 2-hour limited access to a 10% v/v ethanol solution (10E) and water. The acquisition of 10E consumption and underlying drinking patterns were assessed during FIN treatment (7 days) and Subsequent FIN withdrawal (13 days) phases.Results: FIN dose-dependently blocked the acquisition of 10E drinking and prevented the development of ethanol preference, thereby suggesting that the GABAergic neurosteroids may be important in the establishment of stable drinking patterns. FIN-elicited reductions in 10E intake were primarily attributable to selective and marked reductions in bout frequency. as no changes were observed in bout size, duration, or lick rates following FIN treatment. FIN-treated mice continued to exhibit attenuated ethanol consumption after 2 weeks post-treatment, despite a full recovery in brain ALLO levels. A second study confirmed the rightward and downward shift in the acquisition of ethanol intake following 7 daily FIN injections. While there were no significant group differences in brain ALLO levels following the seventh day of ethanol drinking. ALLO levels were decreased by 28% in the FIN-50 group.Conclusions: Although the exact mechanism is unclear. FIN and other pharmacological interventions that modulate the GABAergic system may prove useful in curbing ethanol intake acquisition in at-risk individuals.