Antagonism of 5-hydroxytryptamine_2A receptors attenuates the behavioral effects of cocaine in rats

Serotonin (5-hydroxytryptamine; 5-HT) 5-HT_2A receptors have been shown to modulate dopamine (DA) function and a more thorough appreciation of this modulatory interaction between 5-HT_2A receptors and DA systems may yield insight into novel approaches to treatment of cocaine dependence. The present study examined the effects of two ligands with varying selectivity for 5-HT_2A receptors on the locomotor stimulant and discriminative stimulus effects of cocaine in male rats. Locomotor activity was measured following intraperitoneal injection of vehicle (1 ml/kg), the selective 5-HT_2A receptor antagonist M100907 [R-(+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)] -4-piperidine-methanol] (0.02-2.0 mg/kg), or the 5-HT₂ receptor antagonist ketanserin (0.04-4 mg/kg) 45 min before administration of saline (1 ml/kg) or cocaine (10 mg/kg); monitoring of activity in photobeam chambers began at once and proceeded for 1 h. Neither M100907 nor ketanserin significantly altered basal locomotor activity, but both drugs attenuated cocaine-induced hyperactivity (p < 0.05). In drug discrimination studies, rats were trained to discriminate cocaine (10 mg/kg) from saline (1 ml/kg) in a two-lever, water-reinforced operant task. M 100907 (0.05-1.6 mg/kg) and ketanserin (0.05-4 mg/kg) evoked a dose-related attenuation of the stimulus effects of cocaine (5 mg/kg, p < 0.05). These results suggest that 5-HT_2A receptors play an important role in the behavioral effects of cocaine and that 5-HT_2A receptors should be considered a viable target for analysis in the search for pharmacotherapies useful in the treatment of cocaine dependence.