Discriminative stimulus effects of presynaptic GABA agonists in pentobarbital-trained rats

The discriminative stimulus effects of indirect-acting GABAergic drugs were compared to those of pentobarbital (PB) and midazolam in rats trained to discriminate 5 mg/kg PB from saline under a two-lever fixed-ratio 32 schedule of food reinforcement. PB and midazolam produced dose-dependent substitution for the training dose of PB with response rate reduction only at doses above those producing full substitution. Valproic acid, an antiepileptic drug and GABA transaminase inhibitor, substituted for PB but not only at a dose that produced response rate suppression. Vigabatrin, an irreversible GABA transaminase inhibitor, failed to substitute for PB, but did produce a dose-dependent decrease in response rates. The GABA uptake inhibitors, 1-[2-[bis[4-(trifluoromethyl)phenyl]- methoxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (CI-966) and (R(−)-N-[4,4-bis(3-methylthien-2-yl) but-3-enyl] nipecotic acid HCl (tiagabine), produced no greater than 40% PB-lever responding. Aminoxyacetic acid (AOAA), which is described as a nonselective presynaptic GABA agonist, yielded a maximum of 43% PB-lever responding. These results indicate that the discriminative stimulus effects of the indirect GABAA agonists, PB and midazolam, although similar to one another, differ from those of presynaptic GABAergic drugs. Differences in the discriminative stimulus properties of GABA transaminase inhibitors and uptake inhibitors also exist, indicating that not all presynaptic GABA agonists have similar behavioral profiles. These results contribute to a further understanding of the similarities and differences in the behavioral effects of drugs that enhance GABAergic neurotransmission.