RT Journal Article SR Electronic T1 Antagonism of 5-Hydroxytryptamine2A Receptors Attenuates the Behavioral Effects of Cocaine in Rats JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 357 OP 363 VO 297 IS 1 A1 Lance R. McMahon A1 Kathryn A. Cunningham YR 2001 UL http://jpet.aspetjournals.org/content/297/1/357.abstract AB Serotonin (5-hydroxytryptamine; 5-HT) 5-HT2A receptors have been shown to modulate dopamine (DA) function and a more thorough appreciation of this modulatory interaction between 5-HT2Areceptors 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-HT2Areceptors 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-HT2A 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. M100907 (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-HT2A receptors play an important role in the behavioral effects of cocaine and that 5-HT2Areceptors should be considered a viable target for analysis in the search for pharmacotherapies useful in the treatment of cocaine dependence. The American Society for Pharmacology and Experimental Therapeutics