Neurosteroid modulators of GABA(A) receptors differentially modulate Ethanol intake patterns in male C57BL/6J mice.
Neurosteroid modulators of GABA(A) receptors differentially modulate Ethanol intake patterns in male C57BL/6J mice.
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DOI：
10.1097/01.alc.0000179413.82308.6b
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发表时间：
2005-09-01
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影响因子：
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通讯作者：
Finn, Deborah A
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文献类型：
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作者：
Ford, Matthew M;Nickel, Jeffrey D;Finn, Deborah A
背景：别孕酮(Allo)和结构相关的内源性神经类固醇在生理相关浓度下是γ-氨基丁酸A(GABA(A))受体功能的有效调节剂。越来越多的证据表明，Allo在酒精自我给药、歧视和恢复的行为过程中起着调节作用。本研究的目的是评估外源性神经类固醇激动剂Allo和部分激动剂/拮抗剂表孕酮(EPI)对酒精饮酒模式微结构的影响。方法：雄性C57BL/6J小鼠在黑暗阶段开始后1小时开始的每天2小时的有限接触过程中，通过糖精褪色程序开始饮用无糖的10%v/v乙醇溶液(10E)。用粘度计电路记录了10E和水的累积舔响应。在建立了10个E摄入量基线后，小鼠习惯于车辆注射(VEH；20%w/vβ-环糊精ip)，然后在饮酒前立即接受VEH或神经类固醇治疗。结果：GABA(A)受体阳性调节剂Allo以剂量依赖的方式调节2小时的总酒精摄入量，3.2 mg/kg剂量可显著增加小鼠的酒精摄入量，而24 mg/kg剂量可显著抑制VEH治疗前小鼠的酒精摄入量。等位基因诱发的摄入量改变与发作频率和发作间隔的显著、剂量相关的改变相对应。在最初的5分钟内，ALLO还在10E舔中引起了强劲的、剂量依赖性的升高，但随后在20-80分钟的治疗中产生了10E舔的剂量依赖性抑制。相反，部分激动剂/拮抗剂神经类固醇EPI对所评估的任何消费参数都没有影响。结论：本研究结果表明，GABA(A)受体激活的神经类固醇可能调节调控饮酒发作的开始、维持和终止的调节过程。Allo和EPI对酒精摄入模式的不同影响可能反映了GABA能抑制张力的改变，这可能是由于每种神经类固醇在GABA(A)受体上的药理特征所致。控制内源性等位基因可能被证明是减少过量摄入和防止失去对饮酒的监管控制的有用策略。
BACKGROUND: Allopregnanolone (ALLO) and structurally related endogenous neurosteroids are potent modulators of gamma-aminobutyric acid A (GABA(A)) receptor function at physiologically relevant concentrations. Accumulating evidence implicates a modulatory role for ALLO in behavioral processes underlying ethanol self-administration, discrimination, and reinstatement. The purpose of this study was to evaluate the impact of exogenous neurosteroid challenges with the agonist ALLO and the partial agonist/antagonist epipregnanolone (EPI) on the microarchitecture of ethanol drinking patterns.METHODS: Male C57BL/6J mice were initiated to consume an unsweetened 10% v/v ethanol solution (10 E) by a saccharin fading procedure during daily 2-hr limited-access sessions beginning 1-hr after dark-phase onset. Cumulative lick responses were recorded for 10 E and water by lickometer circuits. After establishing 10 E intake baselines, mice were habituated to vehicle injection (VEH; 20% w/v beta-cyclodextrin ip), and then were treated with either VEH or neurosteroid immediately before the drinking session. Each mouse received a series of ALLO doses (3.2, 10, 17, and 24 mg/kg) alone and EPI doses (0.15, 1, 3, and 10 mg/kg) alone in a counterbalanced within-group design.RESULTS: The GABA(A) receptor-positive modulator ALLO dose-dependently modulated overall ethanol intake throughout the 2-hr session with the 3.2 mg/kg dose eliciting a significant increase, whereas the 24 mg/kg dose produced a significant suppression of ethanol intake versus VEH pretreatment. ALLO-evoked alterations in intake corresponded to significant, dose-dependent alterations in bout frequency and interbout interval. ALLO also elicited robust, dose-dependent elevations in 10 E licks during the initial 5 min of access but subsequently produced in a dose-dependent suppression of 10 E licks during session minutes 20-80. In contrast, the partial agonist/antagonist neurosteroid EPI exhibited no influence on any consumption parameter evaluated.CONCLUSIONS: The present findings suggest that GABA(A) receptor-active neurosteroids may modulate the regulatory processes that govern the onset, maintenance, and termination of drinking episodes. The differential influence of ALLO and EPI on ethanol intake patterns may reflect an alteration in GABA-ergic inhibitory tone that is likely due to each neurosteroid's pharmacological profile at GABA(A) receptors. Manipulation of endogenous ALLO may prove a useful strategy for diminishing excessive intake and protecting against the loss of regulatory control over drinking.