Deletion of the GABA^sub A^ [alpha]2-subunit does not alter self administration of cocaine or reinstatement of cocaine seeking

GABA^sub A^ receptors containing [alpha]2-subunits are highly represented in brain areas that are involved in motivation and reward, and have been associated with addiction to several drugs, including cocaine. We have shown previously that a deletion of the [alpha]2-subunit results in an absence of sensitization to cocaine. We investigated the reinforcing properties of cocaine in GABA^sub A^ [alpha]2-subunit knockout (KO) mice using an intravenous self-administration procedure. [alpha]2-subunit wildtype (WT), heterozygous (HT) and KO mice were trained to lever press for a 30 % condensed milk solution. After implantation with a jugular catheter, mice were trained to lever press for cocaine (0.5 mg/kg/infusion) during ten daily sessions. Responding was extinguished and the mice tested for cue- and cocaine-primed reinstatement. Separate groups of mice were trained to respond for decreasing doses of cocaine (0.25, 0.125, 0.06 and 0.03 mg/kg). No differences were found in acquisition of lever pressing for milk. All genotypes acquired self-administration of cocaine and did not differ in rates of self-administration, dose dependency or reinstatement. However, whilst WT and HT mice showed a dose-dependent increase in lever pressing during the cue presentation, KO mice did not. Despite a reported absence of sensitization, motivation to obtain cocaine remains unchanged in KO and HT mice. Reinstatement of cocaine seeking by cocaine and cocaine-paired cues is also unaffected. We postulate that whilst not directly involved in reward perception, the [alpha]2-subunit may be involved in modulating the "energizing" aspect of cocaine's effects on reward-seeking.[PUBLICATION ABSTRACT]