GABAergic compounds for treating drug addiction: Preclinical models

在2009年10月1日至2010年9月30日期间，该研究项目取得了重大进展。 我们之前发现，γ-氨基丁酸（GABA）转氨酶抑制剂γ-乙烯基-GABA（GVG，Vigabatrin）剂量依赖性地抑制了实验室大鼠中可卡因引发的可卡因寻求行为复发，这些大鼠已被药理学解毒并从行为上消除了他们之前的可卡因服用习惯。 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。 在本报告期间，我们还发现，γ-乙烯基-GABA通过对阴离子通道和GABA转运蛋白的作用，增加了实验室大鼠丘脑核中GABA和谷氨酸的非囊泡释放。 这是一个重要的发现，因为它指出了γ-乙烯基-GABA可能发挥其抗成瘾作用的机制。 这是特别及时的，因为γ-乙烯基-GABA现已进入人体临床试验，以评估其在人体水平上的抗成瘾功效。 我们解释了我们目前的发现（连同我们以前对γ-乙烯基-GABA的发现），表明：1）γ-乙烯基-GABA似乎具有显著的抗成瘾功效; 2）γ-乙烯基-GABA在大脑中的作用机制可能与其他GABA模拟化合物显著不同。 这可以很好地解释我们以前的发现，全身给药加巴喷丁（另一种假定的GABA类化合物，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）对可卡因触发的可卡因寻求行为复发没有影响，加巴喷丁也不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，并且通过体内脑微透析测量，加巴喷丁不能改变丘脑核中的基础或可卡因增强的多巴胺水平。 加上我们之前在各种成瘾相关临床前动物模型中对γ-乙烯基-GABA的广泛研究结果，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，并且在大脑中的作用机制方面可能与其他GABA模拟药物显著不同。

During the period 01 Oct 09 to 30 Sept 10, significant progress was made on this research project. We had previously 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. During the present reporting period, we additionally found that gamma-vinyl-GABA increases nonvesicular release of GABA and glutamate in the nucleus accumbens of laboratory rats via action on anion channels and on GABA transporters. This is an important discovery, as it points toward an uinderstanding of the mechanism(s) by which gamma-vinyl-GABA may exert its anti-addiction effects. This is especially timely, as gamma-vinyl-GABA has now entered human clinical trials to assess its anti-addiction efficacy at the human level. We interpret our current findings (together with our previous findings with gamma-vinyl-GABA) to suggest that: 1) gamma-vinyl-GABA appears to possess significant anti-addiction efficacy; 2) gamma-vinyl-GABA's mechanism(s) of action in the brain may differ significantly from those of other GABAmimetic compounds. This may well explain our previous findings that systemic administration of gabapentin (another putative GABAmimetic compound claimed in some previous reports from other research groups to have anti-cocaine-addiction properties) has no effect on cocaine-triggered relapse to cocaine-seeking behavior, that gabapentin also fails to alter intravenous cocaine self-administration under fixed-ratio reinforcement in laboratory rats, and that gabapentin fails to alter either basal or cocaine-enhanced dopamine levels in the nucleus accumbens as measured by in vivo brain microdialysis. 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, and that it may differ significantly from other GABAmimetic drugs with respect to mechanism(s) of action in the brain.