The yohimbine-induced anticonflict effect in the rat, Part I. Involvement of noradrenergic, serotonergic and endozepinergic(?) mechanisms.

Abstract

The alpha 2-adrenoceptor antagonist yohimbine has in several previous studies been found to produce anticonflict effects comparable to those produced by the benzodiazepines (BDZ) in rat punished conflict models. In this and a following paper we have tried to elucidate the neurochemical mechanisms underlying these effects in a modified Vogel's drinking conflict test. Since yohimbine previously has been demonstrated to interfere both with noradrenaline (NA) and serotonin (5-HT) neurochemistry, and, in addition, shows affinity for the BDZ binding site, we have focused on the putative involvement of these neuronal systems in the yohimbine-induced anticonflict effect. The alpha 2-adrenoceptor agonist clonidine (10 micrograms/kg, i.p.) completely antagonized the anticonflict effect of yohimbine (4.0 mg/kg, i.p.), whereas the alpha 1-adrenoceptor agonist ST 587 (1.0 mg/kg, i.p.) had no effect. The anticonflict effect of yohimbine was totally abolished also following lesioning of NA neurons with 6-hydroxy-dopamine. A high dose of the mixed beta 1 and beta 2 adrenoceptor antagonist propranolol (8.0 mg/kg, i.p.) caused a partial blockade of the yohimbine-induced effect in intact animals, whereas the selective beta 1-adrenoceptor antagonist metoprolol (4.0 mg/kg, i.p.) had no significant effect and the alpha 1-adrenoceptor antagonist prazosin instead potentiated the anticonflict action. The anticonflict effect of yohimbine was dose-dependently antagonized also by the 5-HT precursor L-5-hydroxytryptophan (25-100 mg/kg, i.p.). The BDZ receptor antagonist flumazenil (10 mg/kg, p.o.), as well as Ro 15-4513 (1.0 mg/kg, p.o.), a partial inverse agonist at BDZ receptors, partly, but significantly, counteracted the yohimbine-induced anticonflict effect, whereas low doses of both the chloride channel blocker picrotoxin and the GABAA antagonist bicuculline only tended to counteract the yohimbine effect. Taken together, the results in the present behavioral paper indicate that the anticonflict effect of yohimbine involves both increased NA and decreased 5-HT activity, and that direct or indirect activation of BDZ receptors may also be involved. Neurochemical findings related to these behavioral results are presented in a following paper.