The Gamma-Aminobutyric Acid B Receptor in Depression and Reward

The metabotropic gamma-aminobutyric acid B (GABA_B) 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 GABA_B 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. GABA_B receptor expression and function are enhanced by antidepressants and reduced in animal models of depression. Generally, GABA_B receptor antagonists are antidepressant-like and agonists are pro-depressive. Exceptions to this rule likely reflect the differential influence of GABA_B1 isoforms in depression-related behavior and neurobiology, including the anhedonic effects of social stress. A wealth of data implicate GABA_B receptors in the rewarding effects of drugs of abuse. We focus on nicotine as an example. GABA_B receptor activation attenuates, and deactivation enhances, nicotine reward and associated neurobiological changes. In nicotine withdrawal, however, GABA_B receptor agonists, antagonists, and positive allosteric modulators enhance anhedonia, perhaps owing to differential effects of GABA_B1 isoforms on the dopaminergic system. Nicotine cue-induced reinstatement is more reliably attenuated by GABA_B 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. GABA_B1 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.