Differential Effects of the 5-HT2A Receptor Antagonist M100,907 and the 5-HT2C Receptor Antagonist SB242,084 on Cocaine-induced Locomotor Activity, Cocaine Self-administration and Cocaine-induced Reinstatement of Responding

These studies investigated the effects of antagonists selective for the 5-HT2A, 5-HT2B, or 5-HT2C receptor subtypes on behaviors elicited or maintained by cocaine. The selective 5-HT2A receptor antagonist M100,907 (0.5 mg/kg, SC) attenuated the locomotor activity elicited by 10 mg/kg cocaine, whereas the selective 5-HT2C receptor antagonist SB242,084 (0.5 mg/kg IP) potentiated the locomotor stimulant effect of 10 mg/kg cocaine. The selective 5-HT2B antagonist SB215,505 (3 mg/kg PO) did not alter cocaine-induced locomotor activity. In a second series of experiments, the effects of M100,907 and SB242,084 were examined in rats self-administering cocaine intravenously according to a progressive ratio schedule. M100,907 (0.5–2 mg/kg) did not alter responding for cocaine at an infusion dose of 0.25 mg. Similarly M100,907 (0.5 mg/kg) failed to alter responding for cocaine at infusion doses of 0.0625, 0.125 and 0.25 mg. SB242,084 (0.5–1 mg/kg) increased responding for cocaine with the infusion dose set at 0.125 mg. Examination of the effects of SB242,084 (0.5 mg/kg) on the cocaine dose response curve revealed significant increases in responding at the lowest doses of 0.0625 and 0.125 but not 0.25 mg. After completion of the self-administration experiments responding was extinguished. M100,907 (0.5 mg/kg) attenuated the ability of experimenter administered cocaine (10 mg/kg and 20 mg/kg) to reinstate lever pressing, whereas the priming effect of cocaine (10 mg/kg) was enhanced by SB242,084. These results indicate distinct, and in some cases opposite, effects of a 5-HT2A compared with a 5-HT2C receptor antagonist on various cocaine-mediated behavioral effects.