Modulation of α5 Subunit-Containing GABAA Receptors Alters Alcohol Drinking by Rhesus Monkeys
Modulation of α5 Subunit-Containing GABAA Receptors Alters Alcohol Drinking by Rhesus Monkeys
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DOI：
10.1111/acer.12018
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发表时间：
2013-04-01
影响因子：
3.2
通讯作者：
Platt, Donna M.
中科院分区：
文献类型：
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作者：
Rueedi-Bettschen, Daniela;Rowlett, James K.;Platt, Donna M.
背景：酒精增强γ-氨基丁酸（GABA）在GABAA受体上的活性的能力被认为是酒精行为效应的一个关键机制。这些受体复杂的分子生物学提出了一种可能性，即特定的受体亚型可能在酒精滥用相关效应中发挥独特的作用，并且可能开发出对酒精具有治疗特异性的亚型选择性配体。本研究评估了5GABAA受体配体选择性改变酒精强化作用的能力。方法两组恒河猴在固定比例的时间表和有限的日常接触条件下接受口服自我给药酒精或蔗糖的训练。此外，每日自我给药后，对每只猴的种属典型行为和药物诱导行为进行评分。结果1%~ 6%的酒精浓度可使大鼠维持在高于水的水平上，并产生与酒精浓度相关的90 ~ 160 mg/dl的血液酒精浓度，并产生典型的酒精中毒行为变化。0.3 - 3%蔗糖浓度也能可靠地维持自我给药。5GABAA受体激动剂QH-ii-066增强和5GABAA受体反向激动剂L-655，708抑制酒精，但不抑制蔗糖饮用。5GABAA受体拮抗剂XLi-093可逆转饮酒的变化。然而，L-655，708增加了酒精和蔗糖饮用者的哈欠，可能表明了致焦虑作用。结论5GABAA受体机制在酒精的强化效应中具有重要的作用。此外，这些结果表明，5GABAA受体可能代表了一种新的药理学目标的药物开发，以减少饮酒。在调节该受体的配体中，5GABAA受体反向激动剂可能最有希望作为酒精药物疗法。
Background Alcohol's ability to potentiate the activity of -aminobutyric acid (GABA) at GABAA receptors has been implicated as a key mechanism underlying the behavioral effects of alcohol. The complex molecular biology of these receptors raises the possibility that particular receptor subtypes may play unique roles in alcohol's abuse-related effects and that subtype-selective ligands with therapeutic specificity against alcohol might be developed. This study evaluated the capacity of 5GABAA receptor ligands to alter selectively the reinforcing effects of alcohol. Methods Two groups of rhesus monkeys were trained to orally self-administer alcohol or sucrose under fixed-ratio schedules and limited daily access conditions. In addition, following daily self-administration sessions, the behavior of each monkey was scored for both species-typical and drug-induced behaviors. Results Concentrations of 1 to 6% alcohol maintained self-administration above water levels, engendered pharmacologically relevant blood alcohol levels ranging from 90 to 160mg/dl, and produced changes in behavior typical of alcohol intoxication. Concentrations of 0.3 to 3% sucrose also reliably maintained self-administration. The 5GABAA receptor agonist QH-ii-066 enhanced and the 5GABAA receptor inverse agonist L-655,708 inhibited alcohol, but not sucrose drinking. The changes in alcohol drinking could be reversed with the 5GABAA receptor antagonist XLi-093. However, L-655,708 increased yawning in both alcohol and sucrose drinkers, possibly indicative of an anxiogenic effect. Conclusions These findings suggest a prominent and specific role for 5GABAA receptor mechanisms in the reinforcing effects of alcohol. Moreover, these results suggest that 5GABAA receptors may represent a novel pharmacological target for the development of medications to reduce drinking. Of ligands modulating this receptor, 5GABAA receptor inverse agonists may hold the most promise as alcohol pharmacotherapies.