Dissociation of multiple effects of acute LSD on exploratory behavior in rats by ritanserin and propranolol

Abstract

Rats tested for 1 h in the Behavioral Pattern Monitor (BPM) after injection of the mixed serotonergic agonistd-lysergic acid diethylamide (LSD) exhibit a behavioral profile similar to that produced by various hallucinogenic 5HT-2 agonists. The characteristic effects of the hallucinogens include suppression of locomotor and exploratory behavior and a preferential decrease in entries into the center of the BPM during the initial half of the test session. After LSD, the initial suppression of responding is followed by a subsequent increase in locomotor activity that is not observed with other serotonergic agonists. In the present studies, the 5HT-1 andβ-adrenergic antagonistd,1-propranolol and the 5HT-2 antagonist ritanserin were administered individually or in combination prior to the acute administration of LSD to test for the involvement of these receptor subtypes in the mediation of the effects of LSD in the BPM paradigm. Propranolol (20 mg/kg) abolished the initial suppression of activity induced by 60 µg/kg LSD without affecting the subsequent increase in locomotion. Conversely, 2.0 mg/kg ritanserin failed to block the initial suppressive effects of 60 or 120 µg/kg LSD, but attenuated the LSD-induced increases in activity during the second half of the session. The combination of propranolol and ritanserin prevented both these effects of LSD. By contrast, the more selective 5HT-2 agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) (0.27 mg/kg) produced an initial suppression of activity in the BPM that was blocked by 2.0 mg/kg ritanserin and was not followed by a subsequent increase in activity. These findings suggest that the initial suppressive effects of LSD in the BPM paradigm are dissociable from the subsequent increases in locomotion and that the two effects are mediated via different serotonergic orβ-adrenergic receptors.