Discriminative stimulus effects of ethyl-beta-carboline-3-carboxylate at two training doses in rats

Rationale and objectives: The role of benzodiazepine (BZ) receptor mechanis ms in modulating the stimulus effects of the BZ partial inverse agonist eth yl-beta-carboline-3-carboxylate (beta-CCE) are not well understood. The pur pose of the present experiments was to assess the role of BZ and non-BZ rec eptor stimulation in the discriminative stimulus effects of beta-CCE in rat s. Methods: Adult male rats were trained to discriminate either a relativel y high dose (10 mg/kg, n=8) or a relatively low dose (5.0 mg/kg, n=7) of be ta-CCE from saline under a fixed-ratio 10 schedule of food presentation. Re sults: Under the high-dose training condition, beta-CCE engendered an incre ase in responding on the drug-paired lever up to 100% drug-lever responding , with no decrease in response rate. Diazepam, pentobarbital, flumazenil, ( +)-amphetamine, and morphine did not share stimulus effects with 10 mg/kg b eta-CCE up to doses that suppressed rate of responding. The BZ full inverse agonist dimethoxy-4-ethyl-beta-carboline-3-carboxylate also did not engend er greater than or equal to 80% beta-CCE-lever responding up to doses that suppressed response rate and produced seizures in some animals. The BZ part ial inverse agonists Ro 15-4513 and sarmazenil fully reproduced the stimulu s effects of beta-CCE. Flumazenil antagonized the effects of beta-CCE with an in vivo apparent pA(2) value of 6.1 (slope=-0.86). Under the low-dose co ndition, beta-CCE engendered an increase in drug-lever responding, with no changes in response rate. In contrast to the high-dose condition, diazepam, pentobarbital, and (+)-amphetamine engendered high levels of beta-CCE-leve r responding (up to 77, 96, and 75%, respectively), whereas flumazenil and morphine did not engender full beta-CCE-lever responding. Conclusions: Thes e results indicated that the stimulus effects of the high dose of beta-CCE appeared consistent with mediation by the drug's partial inverse agonist ef fects at BZ receptors. The discriminative stimulus effects of beta-CCE at t he lower training dose, however, appeared to be relatively non-specific.