title: The GABA(A) receptor alpha1 subtype 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.
authors.affiliation: Laboratory of Neuroscience, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Harvey
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Foster
authors.forename: Pete F
authors.initials: PF
authors.lastname: McKay
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Carroll
authors.forename: Regat
authors.initials: R
authors.lastname: Seyoum
authors.forename: James E
authors.initials: JE
authors.lastname: Woods
authors.forename: Collette
authors.initials: C
authors.lastname: Grey
authors.forename: Cecily M
authors.initials: CM
authors.lastname: Jones
authors.forename: Shannan
authors.initials: S
authors.lastname: McCane
authors.forename: Rancia
authors.initials: R
authors.lastname: Cummings
authors.forename: Dynesha
authors.initials: D
authors.lastname: Mason
authors.forename: Chunrong
authors.initials: C
authors.lastname: Ma
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.forename: Harry L
authors.initials: HL
authors.lastname: June
mesh_terms: D000437:Alcoholism / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000037:antagonists & inhibitors; D001667:Binding, Competitive / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D000431:Ethanol / Q000494:pharmacology*; D018756:GABA Antagonists / Q000008:administration & dosage; D018757:GABA Modulators / Q000008:administration & dosage; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D008297:Male; D008845:Microinjections; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits; D018075:RNA, Complementary / Q000008:administration & dosage; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012054:Reinforcement, Psychology; D013574:Synaptosomes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: C454686:3-propoxy-beta-carboline; D002243:Carbolines; D018756:GABA Antagonists; D018757:GABA Modulators; D008024:Ligands; D020033:Protein Isoforms; D021122:Protein Subunits; D018075:RNA, Complementary; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D001569:Benzodiazepines; D000431:Ethanol