Abstract
Serotonin (5-hydroxytryptamine; 5-HT) 5-HT2A receptors have been shown to modulate dopamine (DA) function and a more thorough appreciation of this modulatory interaction between 5-HT2Areceptors and DA systems may yield insight into novel approaches to treatment of cocaine dependence. The present study examined the effects of two ligands with varying selectivity for 5-HT2Areceptors on the locomotor stimulant and discriminative stimulus effects of cocaine in male rats. Locomotor activity was measured following intraperitoneal injection of vehicle (1 ml/kg), the selective 5-HT2A receptor antagonist M100907 [R-(+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol] (0.02–2.0 mg/kg), or the 5-HT2 receptor antagonist ketanserin (0.04–4 mg/kg) 45 min before administration of saline (1 ml/kg) or cocaine (10 mg/kg); monitoring of activity in photobeam chambers began at once and proceeded for 1 h. Neither M100907 nor ketanserin significantly altered basal locomotor activity, but both drugs attenuated cocaine-induced hyperactivity (p< 0.05). In drug discrimination studies, rats were trained to discriminate cocaine (10 mg/kg) from saline (1 ml/kg) in a two-lever, water-reinforced operant task. M100907 (0.05–1.6 mg/kg) and ketanserin (0.05–4 mg/kg) evoked a dose-related attenuation of the stimulus effects of cocaine (5 mg/kg, p < 0.05). These results suggest that 5-HT2A receptors play an important role in the behavioral effects of cocaine and that 5-HT2Areceptors should be considered a viable target for analysis in the search for pharmacotherapies useful in the treatment of cocaine dependence.
Footnotes
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Send reprint requests to: Kathryn A. Cunningham, Ph.D., Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77555-1031. E-mail: cunningham{at}utmb.edu
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This research was supported by National Institute on Drug Abuse Grants DA 05708, DA 06511 (to K.A.C.), and DA 05879 (to L.R.M.). Portions of these data were presented as an abstract at the 29th Annual Meeting of the Society for Neuroscience (Miami, 1999).
- Abbreviations:
- DA
- dopamine
- 5-HT
- 5-hydroxytryptamine
- 5-HT2R
- 5-hydroxytryptamine2 receptor
- M100907
- [R-(+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol]
- FR
- fixed ratio
- MDMA
- (±)-3,4-methylenedioxymeth-amphetamine
- SB 206553
- N-3-pyridinyl-3,5-dihydro-5-methylbenzo(1,2-b:4,5-b′)dipyrrole-1(2H)carboxamide
- Received September 6, 2000.
- Accepted January 10, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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