Interactions of clozapine with the stimulus effects of DOM and LSD.

Two groups of rats were trained with the 5-HT2 agonists 2,5-dimethoxy-4-methylamphetamine (DOM) or lysergic acid diethylamide (LSD) in a two-lever discrimination task. Tests of generalization and antagonism were then carried out with clozapine. DOM did not generalize to clozapine. Partial antagonism of DOM was observed with 0.3, 1, and 2 mg/kg clozapine and statistically significant full antagonism with 3 mg/kg. LSD did not fully generalize to clozapine. Partial antagonism of LSD was observed with 3 and 4 mg/kg clozapine. Because clozapine is known to block muscarinic as well as 5-HT2 receptors, atropine was studied in DOM-trained rats. DOM partially generalized to 3 mg/kg atropine. Partial attenuation of DOM stimulus effects was observed with 3 mg/kg atropine, and no attenuation with 5 mg/kg. A combination of 2 mg/kg clozapine and 3 mg/kg atropine vs. DOM produced response suppression in five of seven rats. The atropine test results do not exclude the possibility of an antimuscarinic component in the observed attenuation of DOM and LSD stimulus effects by clozapine.