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Discriminative stimulus effects of ethyl-beta-carboline-3-carboxylate at two training doses in rats
J K Rowlett1, K M Wilcox, W L Woolverton
1Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson 39216, USA.
Rationale And Objectives:
The role of benzodiazepine (BZ) receptor mechanisms in modulating the stimulus effects of the BZ partial inverse agonist ethyl-beta-carboline-3-carboxylate (beta-CCE) are not well understood. The purpose of the present experiments was to assess the role of BZ and non-BZ receptor stimulation in the discriminative stimulus effects of beta-CCE in rats.
Methods:
Adult male rats were trained to discriminate either a relatively high dose (10 mg/kg, n = 8) or a relatively low dose (5.0 mg/kg, n = 7) of beta-CCE from saline under a fixed-ratio 10 schedule of food presentation.
Results:
Under the high-dose training condition, beta-CCE engendered an increase 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 beta-CCE up to doses that suppressed rate of responding. The BZ full inverse agonist dimethoxy-4-ethyl-beta-carboline-3-carboxylate also did not engender > or = 80% beta-CCE-lever responding up to doses that suppressed response rate and produced seizures in some animals. The BZ partial inverse agonists Ro 15-4513 and sarmazenil fully reproduced the stimulus effects of beta-CCE. Flumazenil antagonized the effects of beta-CCE with an in vivo apparent pA2 value of 6.1 (slope = -0.86). Under the low-dose condition, 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-lever responding (up to 77, 96, and 75%, respectively), whereas flumazenil and morphine did not engender full beta-CCE-lever responding.
Conclusions:
These results indicated that the stimulus effects of the high dose of beta-CCE appeared consistent with mediation by the drug's partial inverse agonist effects at BZ receptors. The discriminative stimulus effects of beta-CCE at the lower training dose, however, appeared to be relatively non-specific.