Discriminative stimulus effect of flesinoxan: effect of 5-HT1A antagonists and PCPA

Rats were trained to discriminate 0.3 mg/kg (IP) flesinoxan from saline in a standard two-lever operant procedure and thereafter subjected to generalization and antagonism tests with the 5-HT1A receptor agonist ipsapirone and the beta-adrenergic/5-HT1 receptor antagonist pindolol. Ipsapirone (3.0 mg/kg) completely substituted for flesinoxan. Both the flesinoxan (0.3 mg/kg) and the ipsapirone cue (3.0 mg/kg) were dose-dependently blocked by (+/-)-pindolol. In a second group of rats, trained to discriminate 0.5 mg/kg (IP) of flesinoxan from saline, the putative 5-HT1A antagonist NAN-190 (in the dose range of 1.0 to 6.0 mg/kg) partially blocked the cue of flesinoxan. Generalization studies revealed that the flesinoxan cue could not be mimicked by NAN-190 (3.0 mg/kg). Finally, rats were pretreated with the 5-HT depletor parachlorophenylalanine (PCPA) and thereafter tested with the flesinoxan training dose (0.5 mg/kg). PCPA pretreatment did not significantly attenuate the recognition of the flesinoxan cue. The present results are in agreement with previous findings concerning the stimulus effect of flesinoxan and point to a mechanism that involves the activation of 5-HT1A receptors in the brain. Depletion of 5-HT did not significantly affect the stimulus effect of flesinoxan, suggesting that presynaptic 5-HT1A receptors do not play a crucial role in the mechanism underlying the stimulus effect of flesinoxan.