Contribution of serotonin (5-HT) 5-HT2 receptor subtypes to the discriminative stimulus effects of cocaine in rats
- 159 Downloads
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.
KeywordsSerotonin receptors Drug discrimination SB 204741 SDZ SER-082 SR 46349B
This research was supported by grants from the US–Poland Joint Commission Maria Sklodowska Curie Fund (MF and KAC), the National Institute on Drug Abuse [DA 06511 (KAC), DA 00260 (KAC), DA 15259 (MJB)], and the statutory activity of the Institute of Pharmacology Polish Academy of Sciences in Crakow (MF). The authors gratefully acknowledge the technical assistance of Ms. Ewa Nowak.
- Di Giovanni G, De Deurwaerdere P, Di Mascio M, Di Matteo V, Esposito E, Spampinato U (1999) Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal dopaminergic function: a combined in vivo electrophysiological and microdialysis study. Neuroscience 91:587–597CrossRefPubMedGoogle Scholar
- Drummond DC, Tiffany ST, Glautier S, Remington B (1995) Addictive behaviour: cue exposure theory and practice. Wiley, West Sussex, EnglandGoogle Scholar
- Fletcher PJ, Grottick AJ, Higgins GA (2002) Differential effects of the 5-HT(2A) receptor antagonist M100907 and the 5-HT(2C) receptor antagonist SB242084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding. Neuropsychopharmacology 27:576–586PubMedGoogle Scholar
- Gobert A, Rivet JM, Lejeune F, Newman-Tancredi A, Adhumeau-Auclair A, Nicolas JP, Cistarelli L, Melon C, Millan MJ (2000) Serotonin(2C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat. Synapse 36:205–221CrossRefPubMedGoogle Scholar
- Rinaldi-Carmona M, Congy C, Santucci V, Simiand J, Gautret B, Neliat G, Labeeuw B, Le Fur G, Soubrie P, Breliere JC (1992) Biochemical and pharmacological properties of SR 46349B, a new potent and selective 5-hydroxytryptamine2 receptor antagonist. J Pharmacol Exp Ther 262:759–768PubMedGoogle Scholar
- Schuster CR, Johanson CE (1988) Relationship between the discriminative stimulus properties and subjective effects of drugs. Psychopharmacology 4:161–175Google Scholar
- Schreiber R, Brocco M, Audinot V, Gobert A, Veiga S, Millan MJ (1995) 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane)-induced head-twitches in the rat are mediated by 5-hydroxytryptamine (5-HT)2A receptors: modulation by novel 5-HT2A/2C antagonists, D1 antagonists and 5-HT1A agonists. J Pharmacol Exp Ther 273:101–112PubMedGoogle Scholar
- Sheskin D (2004) Handbook of parametric and nonparametric statistical procedures. Chapman & Hall/CRC, Boca RatonGoogle Scholar
- Tallarida RJ, Murray RB (1987) Manual of pharmacological calculations with computer programs. Springer Berlin Heidelberg, New YorkGoogle Scholar
- Wise RA, Bozarth MA (1985) Brain mechanisms of drug reward and euphoria. Psychiatry Med 3:445–460Google Scholar