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-HT2AR, 5-HT2BR, and 5-HT2CR) 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-HT2AR agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT2CR 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-HT2AR antagonist SR 46349B [1(Z)-[2-(dimethylamino)ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene] and the preferential 5-HT2CR 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-HT2BR 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-HT2AR 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.
Filip
Malgorzata
M
Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Bubar
Marcy J
MJ
Cunningham
Kathryn A
KA
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D004347:Drug Interactions; D005464:Fluorobenzenes / Q000494:pharmacology; D006948:Hyperkinesis / Q000139:chemically induced*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D010636:Phenols / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D044403:Receptor, Serotonin, 5-HT2B / Q000502:physiology*; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
C092430:1-(5-(2-thenyloxy)-1H-indol-3-yl)propan-2-amine; D000662:Amphetamines; D005464:Fluorobenzenes; D007211:Indoles; D010636:Phenols; D011719:Pyrazines; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013876:Thiophenes; C076033:SR 46349B; C014896:6-chloro-2-(1-piperazinyl)pyrazine; D003042:Cocaine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine