Cellular and Behavioral interactions of gabapentin with alcohol dependence
Cellular and Behavioral interactions of gabapentin with alcohol dependence
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DOI：
10.1523/jneurosci.0575-08.2008
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发表时间：
2008-05-28
影响因子：
5.3
通讯作者：
Koob, George F.
中科院分区：
文献类型：
--
作者：
Roberto, Marisa;Gilpin, Nicholas W.;Koob, George F.
加巴喷丁是 GABA 的结构类似物，具有抗惊厥特性。尽管加巴喷丁具有治疗功效，但其分子和细胞作用机制尚不清楚。杏仁核中央核 (CeA) 的 GABA 能系统在调节自愿乙醇摄入量方面发挥着重要作用。在这里，我们使用乙醇依赖的动物模型研究了加巴喷丁对 CeA 切片中 GABA 能传输、乙醇摄入和焦虑测量的影响。加巴喷丁增加了非依赖大鼠的 CeA 神经元中诱发的 GABA 受体介导的 IPSC (GABA-IPSC) 的振幅，但降低了乙醇依赖大鼠的 CeA 中的振幅。加巴喷丁的作用在特定 GABA(B) 受体拮抗剂的存在下被阻断。长期饮酒后，GABA-IPSC 对 GABA(B) 受体拮抗剂和激动剂的敏感性降低，这表明乙醇诱导的与乙醇依赖相关的 GABA(B) 受体的神经适应可能是长期饮酒后加巴喷丁的不同作用的原因。全身加巴喷丁减少了依赖大鼠的乙醇摄入量，但不减少非依赖大鼠的乙醇摄入量，并使用急性依赖模型逆转了乙醇戒断的焦虑样作用。直接注入 CeA 的加巴喷丁还可以阻断依赖诱导的操作性乙醇反应升高。总的来说，这些发现表明加巴喷丁逆转了乙醇依赖的行为测量，反过来，依赖逆转了加巴喷丁对 CeA 神经元的影响，并表明加巴喷丁是治疗酒精中毒的潜在药物。
Gabapentin is a structural analog of GABA that has anticonvulsant properties. Despite the therapeutic efficacy of gabapentin, its molecular and cellular mechanisms of action are unclear. The GABAergic system in the central nucleus of the amygdala (CeA) plays an important role in regulating voluntary ethanol intake. Here, we investigated the effect of gabapentin on GABAergic transmission in CeA slices, on ethanol intake, and on an anxiety measure using animal models of ethanol dependence. Gabapentin increased the amplitudes of evoked GABA receptor-mediated IPSCs (GABA-IPSCs) in CeA neurons from nondependent rats, but decreased their amplitudes in CeA of ethanol-dependent rats. Gabapentin effects were blocked in the presence of a specific GABA(B) receptor antagonist. The sensitivity of the GABA-IPSCs to a GABA(B) receptor antagonist and an agonist was decreased after chronic ethanol, suggesting that ethanol-induced neuroadaptations of GABA(B) receptors associated with ethanol dependence may account for the differential effects of gabapentin after chronic ethanol. Systemic gabapentin reduced ethanol intake in dependent, but not in nondependent, rats and reversed the anxiogenic-like effects of ethanol abstinence using an acute dependence model. Gabapentin infused directly into the CeA also blocked dependence-induced elevation in operant ethanol responding. Collectively, these findings show that gabapentin reverses behavioral measures of ethanol dependence and, in turn, dependence reverses the effects of gabapentin on CeA neurons, and suggest that gabapentin represents a potential medication for treatment of alcoholism.