| Research Abstract |
Four rhesus monkeys were trained to discriminate ethyl beta-carboline-3-carboxylate(BCCE), an inverse agonist at the benzodiazepine(BZ)receptor, from saline under a two-lever choice, food-reinforcement paradigm. The effect of BCCE at a training dose of 0.18 mg/kg disappeared at 0.032-0.1 mg/kg. When the training dose was lowered to 0.1 mg/kg, the effect disappeared at 0.01-0.032 mg/kg. Thus, sensitivity to the drug is inversely related to the training dose level.
In generalization tests, 8-OHDPAT, a selective agonist at the 5HT1A receptor, and TFMPP, a purported 5HT1B agonist, substituted completely for the effect of BCCE. Spiperone, a 5HT2 and D2 antagonist, did not substitute for BCCE. Haloperidol, a relatively selective D2 antagonist, partially substituted for BCCE. Nicotine, Sch23390, a Dl agonist, and diazepam, a BZ. agonist and a representative anxiolytic, did not substitute for BCCE at any dose up to the dose which suppressed responding.
In antagonism tests, the effect of BCCE at
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0.18 mg/kg disappeared after diazepam at cumulative doses of 0.18 or 10 mg/kg. Pretreatments with the BZ agonist diazepam at 1 mg/kg or the antagonist flumazenil at 0.1 mg/kg, shifted the dose-effect curve of BCCE by 0.25 to 0.75 log units to the right. Pretreatments with Sch23390 at 0.01 mg/kg or TFMPP at 0.01-0.1 mg/kg did not affect the dose-effect of BCCE except that a 0.75 log unit shift to the right was observed after pretreatment with TFMPP in 1 out of 3 monkeys. The antagonism study on 8-OHDPAT revealed that pretreatment with diazepam at 1 mg/kg abolished the substitution of 8-OHDPAT for BCCE, and higher doses of 8-OHDPAT only decreased response. Thus, the antagonism by diazepam of 8-OHDPAT was insurmountable. Pretreatment with flumazenil did not affect the substitution of 8-OHDPAT for BCCE.
These results indicated that the discriminative effect of BCCE in rhesus monkeys represent some but not all aspects of human anxiety, that the effect was primarily mediated by the BZ receptors at the CNS, and that 5HTlA receptors and D2 recetors are also involved in mediating the effect. Less
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