Contribution of serotonin (5-hydroxytryptamine;: 5-HT) 5-HT2 receptor subtypes to the hyperlocomotor effects of cocaine:: Acute and chronic pharmacological analyses

The role of serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor subtypes (5-HT2A R, 5-HT2B R, and 5-HT2C R) in acute cocaine-evoked hyperactivity was compared with their contribution to the development and expression of locomotor sensitization upon repeated, intermittent treatment with cocaine ( 10 mg/kg/day for 5 days) in male Wistar rats. Cocaine-evoked hyperactivity was significantly enhanced by pretreatment with the preferential 5-HT2A R agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT2C R antagonist SDZ SER-082 [(+)-cis-4,5,7a, 8,9,10,11,11a-octahydro-7H-10-methylindolo(1,7-BC)( 2,6) naphthyridine fumarate]. The 5-HT2A R antagonist SR 46349B [1(Z)-[2-(dimethylamino) ethoxyimino]- 1( 2- fluorophenyl)3-( 4-hydroxyphenyl)-2(E)-propene] and the preferential 5- HT2C R agonist MK 212 [6-chloro-2-(1-piperazinyl) pyrazine HCl] ( 2 mg/kg) significantly attenuated acute cocaine-evoked hyperactivity; however, a lower dose of MK 212 (0.3 mg/kg) enhanced cocaine-evoked hyperactivity. The 5-HT2BR agonist BW 723C86 (1-[5-(2-thienylmethoxy)-1H-3-indolyl] propan-2-amine HCl) and the 5-HT2B R antagonist SB 204741 [N-(1-methyl- 5-indolyl)- N'-(3-methyl-5-isothiazolyl) urea] had no effect on cocaine-evoked hyperactivity. Repeated treatment with cocaine alone resulted in a 2-fold increase in hyperactivity upon challenge with cocaine 5 days after termination of the cocaine regimen (sensitization). The 5-HT2A R antagonist SR 46349B also blocked cocaine-evoked hyperactivity following repeated cocaine treatment, whereas the other 5-HT2R ligands were ineffective. When any of the 5-HT2R ligands was coadministered with cocaine during the treatment regimen ( 10 mg/kg/day for 5 days), the development of sensitization was unchanged as measured by the level of cocaine-evoked hyperactivity upon challenge 5 days after termination of the treatment. The present study implies that 5-HT2AR and 5-HT2CR exert oppositional influence upon hyperactivity evoked by acute administration of cocaine; this balance is altered following repeated cocaine administration.