The metabotropic gamma-aminobutyric acid B (GABAB) receptor was the first described obligate G protein-coupled receptor heterodimer and continues to set the stage for discoveries in G protein-coupled receptor signaling complexity. In this review, dedicated to the life and work of Athina Markou, we explore the role of GABAB receptors in depression, reward, and the convergence of these domains in anhedonia, a shared symptom of major depressive disorder and withdrawal from drugs of abuse. GABAB receptor expression and function are enhanced by antidepressants and reduced in animal models of depression. Generally, GABAB receptor antagonists are antidepressant-like and agonists are pro-depressive. Exceptions to this rule likely reflect the differential influence of GABAB1 isoforms in depression-related behavior and neurobiology, including the anhedonic effects of social stress. A wealth of data implicate GABAB receptors in the rewarding effects of drugs of abuse. We focus on nicotine as an example. GABAB receptor activation attenuates, and deactivation enhances, nicotine reward and associated neurobiological changes. In nicotine withdrawal, however, GABAB receptor agonists, antagonists, and positive allosteric modulators enhance anhedonia, perhaps owing to differential effects of GABAB1 isoforms on the dopaminergic system. Nicotine cue-induced reinstatement is more reliably attenuated by GABAB receptor activation. Separation of desirable and undesirable side effects of agonists is achievable with positive allosteric modulators, which are poised to enter clinical studies for drug abuse. GABAB1 isoforms are key to understanding the neurobiology of anhedonia, whereas allosteric modulators may offer a mechanism for targeting specific brain regions and processes associated with reward and depression.

中文翻译：

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抑郁和奖励中的 GABA B 受体

代谢型 γ-氨基丁酸 B (GABAB) 受体是第一个描述的专性 G 蛋白偶联受体异二聚体，并继续为 G 蛋白偶联受体信号传导复杂性的发现奠定基础。在这篇致力于 Athina Markou 生活和工作的评论中，我们探讨了 GABAB 受体在抑郁、奖赏和这些领域在快感缺乏中的融合中的作用，快感缺乏是重度抑郁症和戒断药物滥用的共同症状。GABAB 受体的表达和功能被抗抑郁药增强，而在抑郁症动物模型中则减弱。通常，GABAB 受体拮抗剂是抗抑郁药，激动剂是促抑郁药。该规则的例外情况可能反映了 GABAB1 亚型在抑郁相关行为和神经生物学中的不同影响，包括社会压力的快感效应。大量数据表明 GABAB 受体与滥用药物的奖励作用有关。我们以尼古丁为例。GABAB 受体激活减弱，失活增强尼古丁奖赏和相关的神经生物学变化。然而，在尼古丁戒断中，GABAB 受体激动剂、拮抗剂和正变构调节剂会增强快感缺失，这可能是由于 GABAB1 同种型对多巴胺能系统的不同影响。GABAB 受体激活可以更可靠地减弱尼古丁提示诱导的恢复。使用正变构调节剂可以分离激动剂的期望和不期望的副作用，它们准备进入药物滥用的临床研究。GABAB1 亚型是理解快感缺乏神经生物学的关键，