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) ago nists to substitute for, or alter (i.e. enhance or antagonize), the di scriminative stimulus properties of a moderately low dose of cocaine ( 5 mg/kg) utilizing a two-lever, water-reinforced FR 20 drug discrimina tion procedure in rats. In substitution tests, the 5-HT1A receptor par tial agonists buspirone and gepirone, the 5-HT1A/B receptor agonist RU 24969 and the 5-HT1B/2C receptor agonist m-trifluoromethyl-phenylpipe razine (TFMPP) failed to substitute for the cocaine stimulus, although RU 24969 did engender a maximum of 72% cocaine-lever responding. Fluo xetine (4 mg/kg) engendered primarily saline-appropriate responding. I n combination tests, a fixed dose of either fluoxetine (4 mg/kg), RU 2 4969 (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 o f buspirone co-administered with various doses of cocaine (1.25-10 mg/ kg) engendered a rightward shift in the cocaine dose-response curve. G epirone in combination with cocaine neither enhanced nor antagonized t he 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 stim ulus properties of cocaine in a manner similar to that observed follow ing administration of the 5-HT reuptake inhibitor fluoxetine. The abil ity of buspirone, but not gepirone, to attenuate the cocaine stimulus probably reflects its dopamine (DA) D-2 receptor antagonist properties and not its efficacy at 5-HT1A receptors. (C) 1997 Elsevier Science L td.