Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Curr Top Behav Neurosci. 2022;52:119-155. doi: 10.1007/7854_2020_187.
Metabotropic GABA receptors (GABARs) mediate slow inhibition and modulate synaptic plasticity throughout the brain. Dysfunction of GABARs has been associated with psychiatric illnesses and addiction. Drugs of abuse alter GABA receptor (GABAR) signaling in multiple brain regions, which partly contributes to the development of drug addiction. Recently, GABAR ligands and positive allosteric modulators (PAMs) have been shown to attenuate the initial rewarding effect of addictive substances, inhibit seeking and taking of these drugs, and in some cases, ameliorate drug withdrawal symptoms. The majority of the anti-addiction effects seen with GABAR modulation can be localized to ventral tegmental area (VTA) dopamine neurons, which receive complex inhibitory and excitatory inputs that are modified by drugs of abuse. Preclinical research suggests that GABAR PAMs are emerging as promising candidates for the treatment of drug addiction. Clinical studies on drug dependence have shown positive results with GABAR ligands but more are needed, and compounds with better pharmacokinetics and fewer side effects are critically needed.
代谢型 GABA 受体（GABAR）在整个大脑中介导缓慢的抑制作用，并调节突触可塑性。GABAR 的功能障碍与精神疾病和成瘾有关。滥用药物会改变多个脑区的 GABA 受体（GABAR）信号，这在一定程度上促成了药物成瘾的发展。最近，已经证明 GABA 受体配体和正变构调节剂（PAMs）可以减轻成瘾物质的初始奖赏效应，抑制对这些药物的寻求和摄取，并且在某些情况下，改善药物戒断症状。通过 GABA 调节观察到的大多数抗成瘾作用可以定位于腹侧被盖区（VTA）多巴胺神经元，这些神经元接收复杂的抑制性和兴奋性输入，这些输入会被滥用药物改变。临床前研究表明，GABAR PAMs 正在成为治疗药物成瘾的有希望的候选药物。药物依赖的临床研究显示 GABA 受体配体有积极的结果，但还需要更多的研究，并且迫切需要具有更好的药代动力学和更少副作用的化合物。
