Discriminative stimulus effects of midazolam and abecarnil in rats treated chronically with diazepam or abecarnil

Abstract

Abecarnil (ABC) is a beta-carboline that acts as an agonist at benzodiazepine (BZD) receptors. It possesses anxiolytic and anticonvulsant properties, but produces little sedation and is without muscle relaxant effects. To explain this unusual profile of activity, two hypotheses have been advanced: either 1) ABC acts as a partial agonist or 2) ABC acts as a full agonist, but only at a sub-population of BZD receptors. The present experiment used cross-tolerance profiles between BZDs and ABC to differentiate these hypotheses based upon predictions of receptor theory: tolerance produced to a full agonist should confer even greater cross-tolerance to a partial agonsit. Rats were trained in a three-choice drug discrimination procedure to detect the benzodiazepine, midazolam (MDZ, 1.0 mg/kg) from pentylenetetrazole (PTZ, 20 mg/kg) from saline. Tested acutely, MDZ and ABC substituted for MDZ with similar potencies. Following chronic treatment with the BZD-agonist diazepam (DZP; 20 mg/kg per 8 h for 7 days), both the MDZ and ABC dose-effect curves were significantly shifted to the right, and both drugs showed a comparable three-fold decrease in potency. The chronic administration of ABC (4.0 mg/kg per 8 h for 7 days) produced a different spectrum of results. No significant shift occurred in the MDZ dose-effect curve, but there was a significant seven-fold shift to the right of the ABC dose-effect curve. Throughout all test, PTZ-lever responding rarely occurred and did not account for more than 20% of lever selections for any individual test. These data support the hypothesis that ABC acts as a full agonist at a sub-population of BZD receptors, which mediate its substitution for MDZ.