Contribution of serotonin (5-HT) 5-HT2 receptor subtypes to the discriminative stimulus effects of cocaine in rats.
BACKGROUND
The serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor (5-HT2R) family is an important regulator of the behavioral responsiveness to cocaine.


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Filip
Malgorzata
M
Institute of Pharmacology, Polish Academy of Sciences, 31-343, Cracow, Poland.
Bubar
Marcy J
MJ
Cunningham
Kathryn A
KA
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects; D044403:Receptor, Serotonin, 5-HT2B / Q000187:drug effects; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D012055:Reinforcement Schedule; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013268:Stimulation, Chemical; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
D005464:Fluorobenzenes; D007211:Indoles; C092756:N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl)urea; D009287:Naphthyridines; D010636:Phenols; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C091723:octahydro-7H-10-methylindolo(1,7-bc)(2,6)-naphthyridine; C076033:SR 46349B; D014508:Urea; D003042:Cocaine