Contribution of serotonin (5-HT) 5-HT2 receptor subtypes to the discriminative stimulus effects of cocaine in rats

The serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor (5-HT2R) family is an important regulator of the behavioral responsiveness to cocaine. The present study is an analysis of the role of the 5-HT2R subtypes (5-HT2AR, 5-HT2BR, and 5-HT2CR) in the discriminative stimulus effects of cocaine. Male Wistar rats were trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced FR 20 task, and we investigated the ability of the 5-HT2AR antagonist 1(Z)-[2-(dimethylamino)ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene (SR 46349B), the 5-HT2BR antagonist N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl) urea (SB 204741), and the 5-HT2CR antagonist [(+)-cis -4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo(1,7-bC)(2,6)naphthyridine (SDZ SER-082) to substitute for or to modulate the stimulus effects of cocaine. Pretreatment with SR 46349B (0.5-1 mg/kg) resulted in a rightward shift of the cocaine dose-response curve, while SDZ SER-082 (1 mg/kg) shifted the dose-response for cocaine to the left; SB 204741 (1-3 mg/kg) was inactive. Our pharmacological analyses of selective antagonists of 5-HT2AR, 5-HT2BR, and 5-HT2CR indicate oppositional influence of 5-HT2AR and 5-HT2CR on the stimulus effects of cocaine and exclude a role for the 5-HT2BR. These data suggest that 5-HT2AR and 5-HT2CR may be important in modulating the subjective effects of cocaine in humans.