Modulation of the discriminative stimulus properties of cocaine: comparison of the effects of fluoxetine with 5-HT1A and 5-HT1B receptor agonists.
The present investigation examined the ability of serotonin (5-HT) agonists to substitute for, or alter (i.e. enhance or antagonize), the discriminative stimulus properties of a moderately low dose of cocaine (5 mg/kg) utilizing a two-lever, water-reinforced FR 20 drug discrimination procedure in rats. In substitution tests, the 5-HT1A receptor partial agonists buspirone and gepirone, the 5-HT1A/B receptor agonist RU 24969 and the 5-HT1B/2C receptor agonist m-trifluoromethyl-phenylpiperazine (TFMPP) failed to substitute for the cocaine stimulus, although RU 24969 did engender a maximum of 72% cocaine-lever responding. Fluoxetine (4 mg/kg) engendered primarily saline-appropriate responding. In combination tests, a fixed dose of either fluoxetine (4 mg/kg), RU 24969 (0.5 mg/kg) or TFMPP (0.5 mg/kg) produced a leftward shift in the cocaine dose-response curve (0.313-5 mg/kg). In contrast, buspirone (2.5-20 mg/kg) resulted in a dose-dependent attenuation (approximately 60% reduction) of the cocaine stimulus. Moreover, a dose of 10 mg/kg of buspirone co-administered with various doses of cocaine (1.25-10 mg/kg) engendered a rightward shift in the cocaine dose-response curve. Gepirone in combination with cocaine neither enhanced nor antagonized the cocaine discriminative stimulus. Whereas 5-HT agonists do not fully substitute for cocaine, the present results demonstrate that 5-HT1B, but not 5-HT1A, receptor agonists can modulate the discriminative stimulus properties of cocaine in a manner similar to that observed following administration of the 5-HT reuptake inhibitor fluoxetine. The ability of buspirone, but not gepirone, to attenuate the cocaine stimulus probably reflects its dopamine (DA) D2 receptor antagonist properties and not its efficacy at 5-HT1A receptors.
Callahan
P M
PM
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555, U.S.A.
Cunningham
K A
KA
D000818:Animals; D002065:Buspirone / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D017366:Serotonin Receptor Agonists; D005473:Fluoxetine; D003042:Cocaine; D002065:Buspirone