Disruption of Operant Oral Self-Administration of Ethanol, Sucrose, and Saccharin by the AMP/Kainate Antagonist, NBQX, but Not the AMPA Antagonist, GYKI 52466

Abstract

AMPAergic transmission has been suggested to be important in mediating the rewarding effects of drugs. We therefore examined the role of non-NMDA glutamate-receptors in mediating the reinforcing properties of ethanol in an oral self-administration paradigm. The competitive antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline) and the non-competitive antagonist, GYKI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylene-dioxy-5H2,3- be nzodiazepine), were administered to animals previously trained to self-administer ethanol, sucrose, or saccharin, on a progressive ratio schedule. GYKI 52466 (5 & 10 mg/kg) had no effect on operant responding for ethanol, but increased spontaneous locomotor activity, whereas the highest doses of NBQX (3 & 6 mg/kg) significantly decreased operant responding and correspondingly decreased the breaking point in responding for ethanol on a progressive ratio schedule. NBQX (but not GYKI 52466) also significantly decreased operant responding for a food reinforcer (sucrose) as well as for a sweet tasting reinforcer (saccharin). Doses of NBQX that disrupted operant performance caused a significant reduction in locomotor activity, indicating that NBQX decreased ethanol self-administration only at doses which disrupt motor activity. These results suggest non-NMDA glutamate-receptors may not have a specific role in the maintenance of responding for an ethanol reinforcer, but may generally disrupt operant performance. Because, unlike GYKI 52466, NBQX possesses an action at central kainate receptors, these results suggest that kainate, but not AMPA (alpha-amino 3-hydroxy-5-methyl-4-isoxazole propionate) receptors may be important in mediating the reinforcing effects of ethanol.