Detailed investigations of 5-HT3 compounds in a drug discrimination model

Serotonin type-3 (5-HT3) receptors modulate both dopamine (DA) release and locomotor stimulation induced by cocaine, yet appear to be ineffective at blocking its stimulus and reinforcing effects. To more thoroughly characterize a potential modulatory role of 5-HT3 receptors in the stimulus effects of cocaine, rats (n = 8/group) were trained to discriminate cocaine (10 mg/kg, IP) or the 5-HT3 agonist 1-(meta-chlorophenyl)-biguanide (mCPBG: 15 mg/kg, IP) from saline using a standard drug discrimination task. In rats trained to discriminate cocaine, mCPBG (2.5-20 mg/kg) produced, at best, a partial substitution while mCPBG (10 mg/kg) did not alter the cocaine dose-response relationship. The 5-HT3 antagonists MDL 72222 (10 mg/kg) and ondansetron (1.25-16 mg/kg) did not attenuate the cocaine cue. In rats trained to discriminate mCPBG from saline, the 5-HT precursor l-5-hydroxytryptophan (12.5-50 mg/kg) dose-dependently substituted for mCPBG, whereas the 5-HT3 antagonist zacopride (0.1-10 mg/kg) partially antagonized the mCPBG cue, demonstrating that mCPBG produces distinct discriminable effects that appear to be mediated by 5-HT, possibly 5-HT3, receptors. However, cocaine (5-20 mg/kg) did not substitute in mCPBG-trained rats. Overall, these data support previous findings to suggest that 5-HT3 receptors play little role in mediating the discriminative stimulus effects of cocaine and suggest that the neurochemical mechanisms and/or sites of action important for the generation of the discriminative stimulus vs. locomotor stimulatory effects of cocaine may be dissociable.