Antagonism of 5-hydroxytryptamine(2a) receptors attenuates the behavioral effects of cocaine in rats.
Serotonin (5-hydroxytryptamine; 5-HT) 5-HT(2A) receptors have been shown to modulate dopamine (DA) function and a more thorough appreciation of this modulatory interaction between 5-HT2A receptors 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-HT2A receptors 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-HT(2) 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-HT2A receptors should be considered a viable target for analysis in the search for pharmacotherapies useful in the treatment of cocaine dependence.
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77555-1031, USA.
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McMahon
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Cunningham
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D004193:Discrimination Learning / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D005464:Fluorobenzenes / Q000494:pharmacology*; D007650:Ketanserin / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*
D005464:Fluorobenzenes; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D007650:Ketanserin; C079049:volinanserin; D003042:Cocaine; D004298:Dopamine