GABAB receptors are ubiquitous G protein-coupled receptors that are heterodimers of GABAB1 and GABAB2 subunits. Presynaptic GABAB receptors repress Ca2+ influx, and therefore GABA release, by inhibiting the activity of voltage-gated calcium channels [33], [34]. In interpreting the results of our study it should be borne in mind that we only measured mRNA transcripts and not protein levels, however if decreased GABBR1 expression results in down-regulation of GABAB receptors our identical findings in alcoholics, cocaine addicts and alcohol-naïve P rats suggest that this may be a marker for vulnerability to addiction. Indeed, accumulating evidence from studies in mice and rats (including Indiana P rats) shows that in the reverse situation of GABAB receptor up-regulation by agonists such as baclofen, there is a reduction of drug-related behaviors including alcohol consumption, relapse-like drinking and re-instatement of cocaine seeking behavior [17], [18], [35], [36], [37]. Moreover, baclofen decreases alcohol consumption, craving and severity of alcohol withdrawal symptoms in humans [17], [19]. By inference, down-regulation of GABAB receptors may increase the rewarding effects of drugs of abuse.
