Dewey S L, Morgan A E, Ashby C R, Horan B, Kushner S A, Logan J, Volkow N D, Fowler J S, Gardner E L, Brodie J D
Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
Synapse. 1998 Oct;30(2):119-29. doi: 10.1002/(SICI)1098-2396(199810)30:2<119::AID-SYN1>3.0.CO;2-F.
Cocaine's addictive liability has been linked to its pharmacologic actions on mesotelencephalic dopamine (DA) reinforcement/reward pathways in the central nervous system (CNS). Dopaminergic transmission within these pathways is modulated by gamma-aminobutyric acid (GABA). With this knowledge, we examined the utility of gamma vinylGABA (GVG), a selective and irreversible inhibitor of GABA-transaminase (GABA-T) known to potentiate GABAergic inhibition, to alter cocaine's biochemical effects as well as its effects on behaviors associated with these biochemical changes. GVG significantly attenuated cocaine-induced increases in neostriatal synaptic DA in the non-human primate (baboon) brain as assessed by positron emission tomography (PET) and abolished both the expression and acquisition of cocaine-induced conditioned place preference (CPP). It had no effect on CPP for a food reward, the delivery of cocaine to the brain or locomotor activity. These findings suggest the possible therapeutic utility in cocaine addiction of a pharmacologic strategy targeted at the GABAergic neurotransmitter system, a system distinct from but functionally linked to the DA mesotelencephalic reward/reinforcement system. However, rather than targeting the GABA receptor complex with a direct GABA agonist, this novel approach with GVG takes advantage of the prolonged effects of an irreversible enzyme inhibitor that raises endogenous GABA levels without the addictive liability associated with GABA agonists acting directly at the receptor itself. Human trials with GVG are currently being developed to directly examine the utility of this novel strategy for the treatment of cocaine addiction.
可卡因的成瘾性与其对中枢神经系统（CNS）中脑边缘多巴胺（DA）强化/奖赏通路的药理作用有关。这些通路内的多巴胺能传递受γ-氨基丁酸（GABA）调节。基于这一认识，我们研究了γ-乙烯基GABA（GVG）的效用，它是一种已知能增强GABA能抑制作用的GABA转氨酶（GABA-T）的选择性不可逆抑制剂，用于改变可卡因的生化效应及其对与这些生化变化相关行为的影响。通过正电子发射断层扫描（PET）评估，GVG显著减弱了可卡因诱导的非人类灵长类动物（狒狒）大脑新纹状体突触DA的增加，并消除了可卡因诱导的条件性位置偏爱（CPP）的表达和习得。它对食物奖赏的CPP、可卡因向大脑的递送或运动活动没有影响。这些发现表明，针对GABA能神经递质系统的药理策略在可卡因成瘾治疗中可能具有治疗效用，该系统与DA中脑边缘奖赏/强化系统不同但功能相关。然而，这种使用GVG的新方法并非用直接的GABA激动剂靶向GABA受体复合物，而是利用不可逆酶抑制剂的延长效应来提高内源性GABA水平，而不存在与直接作用于受体本身的GABA激动剂相关的成瘾性。目前正在开展GVG的人体试验，以直接检验这种新策略治疗可卡因成瘾的效用。
