GABAergic compounds-treating drug addiction: Preclinical

在2004年10月1日至2005年9月30日期间，该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）剂量依赖性地抑制可卡因引发的可卡因寻求行为复发的实验室大鼠已被脱毒，并从他们以前的可卡因服用习惯的行为熄灭。与γ-乙烯基-GABA相反，全身给予加巴喷丁（另一种在以前的一些研究中声称对可卡因依赖具有抗成瘾特性的化合物）被发现对可卡因引发的可卡因寻求或可卡因服用行为的复发没有任何影响。通过使用体内脑微透析，我们进一步发现γ-乙烯基-GABA剂量依赖性地抑制可卡因诱导的边缘前脑伏核细胞外谷氨酸的增加，但不影响可卡因诱导的伏核细胞外多巴胺的增加边缘前脑。我们进一步发现，加巴喷丁对延髓核细胞外多巴胺或谷氨酸都没有影响。当添加到我们以前对γ-乙烯基-GABA的广泛研究结果时，本研究结果表明γ-乙烯基-GABA可能在人类药物成瘾中具有抗成瘾，抗渴望和抗复发功效。

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.