GABAergic compounds for treating drug addiction: Preclinical models

在2007年10月1日至2008年9月30日期间，该研究项目取得了重大进展。 我们发现，γ-氨基丁酸（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，这些大鼠已被脱毒并从先前的可卡因服用习惯中行为消失。 我们进一步发现，γ-乙烯基-GABA也剂量依赖性地抑制蔗糖诱导的大鼠奖励寻求行为的恢复。 通过使用在体脑微透析，我们还发现，γ-乙烯基-GABA剂量依赖性地提高细胞外GABA水平的边缘前脑的脑桥核。 然而，γ-乙烯基-GABA，无论是全身或局部给药到脑桥核，未能抑制基础或可卡因增强的脑桥核多巴胺，无论是在药物幼稚大鼠或可卡因灭绝大鼠。 我们将这些发现解释为：1）γ-乙烯基-GABA显著抑制可卡因或蔗糖触发的奖赏寻求行为复发; 2）γ-乙烯基-GABA对可卡因触发的药物寻求行为复发的拮抗作用，至少就γ-乙烯基-GABA在丘脑核内的作用而言，是依赖于GABA能而非多巴胺能的脑机制。 与γ-乙烯基-GABA相反，发现全身给予加巴喷丁（另一种在其他研究小组的一些先前报告中声称具有抗可卡因成瘾特性的假定GABA模拟化合物）对可卡因触发的可卡因寻求行为复发没有影响。 加巴喷丁也未能改变实验室大鼠在固定比例强化下的静脉内可卡因自我给药。 在体内脑微透析实验表明，加巴喷丁产生一个温和的（50%）增加细胞外GABA水平的核延髓，但未能改变基础或可卡因增强多巴胺水平的核延髓。 当添加到我们之前在各种成瘾相关的临床前动物模型中使用γ-乙烯基-GABA的广泛发现时，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。 然而，加巴喷丁似乎缺乏显著的抗成瘾、抗渴望或抗复发功效。

During the period 01 Oct 07 to 30 Sept 08, significant progress was made on this research project. We found that the gamma-aminobutyric acid (GABA) transaminase inhibitor gamma-vinyl-GABA (GVG, Vigabatrin) dose-dependently inhibits cocaine-triggered relapse to cocaine-seeking behavior in laboratory rats who have been pharmacologically detoxified and behaviorally extinguished from their prior cocaine-taking habits. We further found that gamma-vinyl-GABA also dose-dependently inhibits sucrose-induced reinstatement of reward-seeking behavior in rats. By using in vivo brain microdialysis, we additionally found that gamma-vinyl-GABA dose-dependently elevates extracellular GABA levels in the nucleus accumbens of the limbic forebrain. However, gamma-vinyl-GABA, when administered either systemically or locally into the nucleus accumbens, fails to inhibit either basal or cocaine-enhanced nucleus accumbens dopamine in either drug-naive rats or in cocaine-extinction rats. We interpret these findings to suggest that: 1) gamma-vinyl-GABA significantly inhibits cocaine- or sucrose-triggered relapse to reward-seeking behavior; and 2) a GABAergic-, but not dopaminergic-, dependent brain mechanism underlies the antagonism by gamma-vinyl-GABA of cocaine-triggered reinstatement of drug-seeking behavior, at least with respect to gamma-vinyl-GABA's action(s) within the nucleus accumbens. In contrast to gamma-vinyl-GABA, systemic administration of gabapentin (another putative GABAmimetic compound claimed in some previous reports from other research groups to have anti-cocaine-addiction properties) was found to have no effect on cocaine-triggered relapse to cocaine-seeking behavior. Gabapentin also failed to alter intarvenous cocaine self-administration under fixed-ratio reinforcement in laboratory rats. In vivo brain microdialysis experiments showed that gabapentin produces a modest (50%) increase in extracellular GABA levels in the nucleus accumbens, but fails to alter either basal or cocaine-enhanced dopamine levels in the nucleus accumbens. When added to our previous extensive findings with gamma-vinyl-GABA in a very wide variety of addiction-related preclinical animal models, the present findings suggest that gamma-vinyl-GABA may have anti-addiction, anti-craving, and anti-relapse efficacy in human drug addiction. However, gabapentin appears to lack significant anti-addiction, anti-craving, or anti-relapse efficacy.