GABAA Receptors Containing α5 Subunits in the CA1 and CA3 Hippocampal Fields Regulate Ethanol-Motivated Behaviors: An Extended Ethanol Reward Circuitry

GABA receptors within the mesolimbic circuitry have been proposed to play a role in regulating alcohol-seeking behaviors in the alcohol-preferring (P) rat. However, the precise GABAAreceptor subunit(s) mediating the reinforcing properties of EtOH remains unknown. We examined the capacity of intrahippocampal infusions of an α5 subunit-selective (∼75-fold) benzodiazepine (BDZ) inverse agonist [i.e., RY 023 (RY) (tert-butyl 8-(trimethylsilyl) acetylene-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate)] to alter lever pressing maintained by concurrent presentation of EtOH (10% v/v) and a saccharin solution (0.05% w/v). Bilateral (1.5–20 μg) and unilateral (0.01–40 μg) RY dose-dependently reduced EtOH-maintained responding, with saccharin-maintained responding being reduced only with the highest doses (e.g., 20 and 40 μg). The competitive BDZ antagonist ZK 93426 (ZK) (7 μg) reversed the RY-induced suppression on EtOH-maintained responding, confirming that the effect was mediated via the BDZ site on the GABAA receptor complex. Intrahippocampal modulation of the EtOH-maintained responding was site-specific; no antagonism by RY after intra-accumbens [nucleus accumbens (NACC)] and intraventral tegmental [ventral tegmental area (VTA)] infusions was observed. Because the VTA and NACC contain very high densities of α1 and α2 subunits, respectively, we determined whether RY exhibited a “negative” or “neutral” pharmacological profile at recombinant α1β3γ2, α2β3γ2, and α5β3γ2 receptors expressed in Xenopus oocytes. RY produced “classic” inverse agonism at all α receptor subtypes; thus, a neutral efficacy was not sufficient to explain the failure of RY to alter EtOH responding in the NACC or VTA. The results provide the first demonstration that the α5-containing GABAA receptors in the hippocampus play an important role in regulating EtOH-seeking behaviors.

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