GABAB receptors in reward processes

Abstract

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.