GABAergic compounds-treating drug addiction: Preclinical

在2004年10月1日至2005年9月30日期间，这一研究项目取得了适度进展。我们发现，GABA转氨酶抑制剂γ-乙烯基-GABA(GVG，Vigabatrin)可剂量依赖性地抑制实验大鼠因可卡因引发的寻求可卡因行为的复发，这些大鼠已被药物戒毒，并从先前的可卡因服用习惯中行为消失。与伽马-乙烯-GABA相反，全身服用加巴喷丁(另一种化合物，在之前的一些研究中声称具有抗可卡因依赖的成瘾特性)被发现对可卡因引发的寻求可卡因或吸食可卡因的行为复发没有任何影响。通过在体脑微透析，我们进一步发现，γ-乙烯-GABA剂量依赖性地抑制可卡因诱导的边缘前脑伏隔核细胞外谷氨酸的增加，但不影响可卡因诱导的边缘前脑伏隔核细胞外多巴胺的增加。我们进一步发现，加巴喷丁对伏核中的细胞外多巴胺或谷氨酸都没有影响。加上我们之前对伽马-乙烯-GABA的广泛发现，目前的发现表明，伽马-乙烯-GABA可能在人类药物成瘾中具有抗成瘾、抗渴求和抗复发的功效。

During the period 01 Oct 04 to 30 Sept 05, moderate progress was made on this research project. We found that the GABA transaminase inhibitor gamma-vinyl-GABA (GVG, Vigabatrin) dose-dependently inhibits cocaine-triggered relapse to cocaine-seeking behavior in laboratory rats who has been pharmacologically detoxified and behaviorally extinguished from their prior cocaine-taking habits. In contrast to gamma-vinyl-GABA, systemic administration of gabapentin (another compound claimed in some previous studies to have anti-addiction properties for cocaine dependence) was found to have no effect whatever on cocaine-triggered relapse to cocaine-seeking or cocaine-taking behavior. By using in vivo brain microdialysis, we further found that gamma-vinyl-GABA dose-dependently inhibits the cocaine-induced increase in extracellular glutamate in the nucleus accumbens of the limbic forebrain, but does not affect the cocaine-induced increase in extracellular dopamine in the nucleus accumbens of the limbic forebrain. We further found that gabapentin has no effect on either extracellular dopamine or glutamate in the nucleus accumbens. When added to our previous extensive findings with gamma-vinyl-GABA, the present findings suggest that gamma-vinyl-GABA may have anti-addiction, anti-craving, and anti-relapse efficacy in human drug addiction.