The GABA_AReceptor α₁Subtype in the Ventral Pallidum Regulates Alcohol-Seeking Behaviors

Abstract

We investigated the potential role of the alpha1-containing GABA(A) receptor in regulating the reinforcing properties of alcohol. To accomplish this, we developed 3-propoxy-beta-carboline hydrochloride (3-PBC), a mixed agonist-antagonist benzodiazepine site ligand with binding selectivity at the alpha1 receptor. We then tested the capacity of 3-PBC to block alcohol-maintained responding in the ventral pallidum (VP), a novel alcohol reward substrate, which primarily expresses the alpha1-receptor isoform. Our results demonstrated that bilateral microinfusion of 3-PBC (0.5-40 microg) in the anterior and medial VP produced marked reductions in alcohol-maintained responding in a genetically selected rodent model of alcohol drinking. The VP infusions showed both neuroanatomical and reinforcer specificity because no effects were seen in sites dorsal to the VP (e.g., nucleus accumbens, caudate putamen). The saccharin-maintained responding was reduced only with the highest dose (40 microg). Parenteral injections of 3-PBC (1-20 mg/kg) also showed a similar selectivity on alcohol-maintained responding. Complementary in vitro studies revealed that 3-PBC exhibited a low partial agonist efficacy profile at recombinant diazepam-sensitive receptors (e.g., alpha1beta3gamma2, alpha2beta3gamma, and alpha3beta3gamma2). The selective suppression of 3-PBC on alcohol-maintained responding after central and parenteral administrations, together with its low-efficacy agonist profile, suggest that the reduction in alcohol-maintained behaviors was not attributable to a general suppression on consummatory behaviors. These results demonstrate that the alpha1-containing GABA(A) receptors in both the anterior and medial VP are important in regulating the reinforcing properties of alcohol. These receptors represent novel targets in the design and development of pharmacotherapies for alcohol-dependent subjects.

GABAA and Opioid Receptors of the Central Nucleus of the Amygdala Selectively Regulate Ethanol-Maintained Behaviors

“…Rats were trained to lever press for EtOH (10% v/v), using a modified version of the sucrose fading technique June, 2002;Harvey et al, 2002). For all training protocols, animals were water-deprived on the first 3 days of training, using a 23 h fluid deprivation schedule to facilitate lever-pressing.…”

“…Research on the neuroanatomical basis of alcohol reward has shown that the nucleus accumbens (NACC), ventral tegmental area (VTA), ventral pallidum (VP), central amygdala (CeA), and hippocampus are involved in GABAergic regulation of ethanol (EtOH) reinforcement (Hyytiä and Koob, 1995;Nowak et al, 1998;June et al, 1998aJune et al, , b, 2001Harvey et al, 2002). Opioidergic neurons within the NACC, CeA, and basolateral amygdala (BLA) have also been shown to regulate EtOH reinforcement (Heyser et al, 1999;Hyytiä and Kiianmaa, 2001).…”

“…Specifically, the a1 subtype in the anterior and medial VP (Harvey et al, 2002) and the a5 isoform in the CA1 and CA3 hippocampus (HPC) ) have both been shown to be important mediators of alcohol reinforcement. Unlike the VP and HPC, equivocal research exists on the primary type of isoform within the CeA.…”

“…b-carboline-3-carboxylate-t-butyl ester (bCCt) is a mixed benzodiazepine agonist-antagonist ligand with binding selectivity at the a1 receptor (Cox et al, 1995;Carroll et al, 2001;Harvey et al, 2002). However, bCCt also exhibits some affinity (albeit lower) for both the a2 and a3 receptors (Cox et al, 1995;Carroll et al, 2001;Harvey et al, 2002) (for a review, see Harvey et al, 2002).…”

“…However, bCCt also exhibits some affinity (albeit lower) for both the a2 and a3 receptors (Cox et al, 1995;Carroll et al, 2001;Harvey et al, 2002) (for a review, see Harvey et al, 2002). Behavioral studies in several species (eg, rats, mice, primates) show that bCCt is a BDZ antagonist exhibiting competitive binding site interaction with BDZ agonists over a broad range of doses (Shannon et al, 1984;Griebel et al, 1999;Cox et al, 1998;Carroll et al, 2001Carroll et al, , 1991Rowlett et al, 2001;Paronis et al, 2001).…”