Roberto Marisa, Gilpin Nicholas W, O'Dell Laura E, Cruz Maureen T, Morse Andrew C, Siggins George R, Koob George F
Committee on the Neurobiology of Addictive Disorders, Pearson Center for Alcoholism and Addiction Research, The Scripps Research Institute, La Jolla, California 92037, USA.
J Neurosci. 2008 May 28;28(22):5762-71. doi: 10.1523/JNEUROSCI.0575-08.2008.
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.
加巴喷丁是一种具有抗惊厥特性的γ-氨基丁酸（GABA）结构类似物。尽管加巴喷丁具有治疗效果，但其分子和细胞作用机制尚不清楚。杏仁核中央核（CeA）中的GABA能系统在调节自愿乙醇摄入中起重要作用。在此，我们使用乙醇依赖动物模型研究了加巴喷丁对CeA切片中GABA能传递、乙醇摄入以及焦虑指标的影响。加巴喷丁增加了非依赖大鼠CeA神经元中诱发的GABA受体介导的抑制性突触后电流（GABA-IPSCs）的幅度，但降低了乙醇依赖大鼠CeA中其幅度。在存在特异性GABA(B)受体拮抗剂的情况下，加巴喷丁的作用被阻断。慢性乙醇处理后，GABA-IPSCs对GABA(B)受体拮抗剂和激动剂的敏感性降低，这表明与乙醇依赖相关的乙醇诱导的GABA(B)受体神经适应性变化可能解释了慢性乙醇处理后加巴喷丁的不同作用。全身性加巴喷丁减少了依赖大鼠而非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致焦虑样效应。直接注入CeA的加巴喷丁也阻断了依赖诱导的操作性乙醇反应升高。总体而言，这些发现表明加巴喷丁逆转了乙醇依赖的行为指标，反过来，依赖也逆转了加巴喷丁对CeA神经元的作用，并表明加巴喷丁代表了一种治疗酒精中毒的潜在药物。
