Vlachou Styliani, Markou Athina
Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, California, USA.
Adv Pharmacol. 2010;58:315-71. doi: 10.1016/S1054-3589(10)58013-X.
gamma-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the brain which acts through different receptor subtypes. Metabotropic GABA(B) receptors are widely distributed throughout the brain. Alterations in GABA signaling through pharmacological activation or deactivation of the GABA(B) receptor regulate behavior and brain reward processes. GABA(B) receptor agonists and, most recently, positive modulators have been found to inhibit the reinforcing effects of drugs of abuse, such as cocaine, amphetamine, nicotine, ethanol, and opiates. This converging evidence of the effects of GABA(B) compounds on the reinforcing properties of addictive drugs is based on behavioral studies that used a variety of procedures with relevance to reward processes and drug abuse liability, including intracranial self-stimulation, intravenous self-administration under both fixed- and progressive-ratio schedules of reinforcement, reinstatement, and conditioned place preference. GABA(B) receptor agonists and positive modulators block the reinforcing effects of drugs of abuse in these animal models. However, GABA(B) receptor agonists also have undesirable side-effects. GABA(B) receptor modulators have potential advantages as medications for drug addiction. These compounds have a better side-effect profile than GABA(B) agonists because they are devoid of intrinsic agonistic activity in the absence of GABA. They only exert their modulatory actions in concert with endogenous GABAergic activity. Thus, GABA(B) receptor positive modulators are promising therapeutics for the treatment of various aspects of dependence (e.g., initiation, maintenance, and relapse) on various drugs of abuse, such as cocaine, nicotine, heroin, and alcohol.
γ-氨基丁酸（GABA）是大脑中主要的抑制性神经递质，通过不同的受体亚型发挥作用。代谢型GABA(B)受体广泛分布于整个大脑。通过药物激活或失活GABA(B)受体来改变GABA信号传导，可调节行为和大脑奖赏过程。已发现GABA(B)受体激动剂以及最近的正向调节剂可抑制滥用药物（如可卡因、苯丙胺、尼古丁、乙醇和阿片类药物）的强化作用。关于GABA(B)化合物对成瘾药物强化特性影响的这一趋同证据，是基于行为学研究得出的，这些研究采用了多种与奖赏过程和药物滥用倾向相关的实验程序，包括颅内自我刺激、固定比率和累进比率强化程序下的静脉自我给药、复吸以及条件性位置偏爱。在这些动物模型中，GABA(B)受体激动剂和正向调节剂可阻断滥用药物的强化作用。然而，GABA(B)受体激动剂也有不良副作用。GABA(B)受体调节剂作为治疗药物成瘾的药物具有潜在优势。这些化合物的副作用比GABA(B)激动剂更好，因为在没有GABA的情况下它们没有内在激动活性。它们仅与内源性GABA能活性协同发挥调节作用。因此，GABA(B)受体正向调节剂有望用于治疗对各种滥用药物（如可卡因、尼古丁、海洛因和酒精）的不同方面（如起始、维持和复发）的依赖。
