Two-lever drug–drug discrimination with the 5-HT1 receptor agonists flesinoxan and eltoprazine

Previous drug discrimination studies with the 5-HT1 receptor agonists flesinoxan and eltoprazine showed a clear 5-HT1A receptor-mediated effect for flesinoxan and the involvement of both 5-HT1A and 5-HT1B receptors in eltoprazine. However, there was no clear antagonism of eltoprazine's cue, possibly due to the compound nature of the eltoprazine stimulus. In the present experiments, in order to create a specific 5-HT1A vs. 5-HT1B receptor-mediated discrimination, rats were trained to discriminate between flesinoxan and eltoprazine. All rats learned the discrimination readily (mean = 41.3 sessions to criterion). With training doses of 1.0 mg/kg, p.o. flesinoxan and 1.5 mg/kg, p.o. eltoprazine, saline administration resulted in 50% of the responses made on both levers. Substitution tests showed that the flesinoxan stimulus was mediated by the 5- HT1A receptor (8-OH-DPAT, buspirone) and the eltoprazine stimulus probably mediated by the 5-HT1B receptor (anpirtoline, TFMPP, RU-24969). The selective 5-HT1A receptor antagonist WAY-100635 antagonized the flesinoxan cue, and the discriminative stimulus of eltoprazine could be completely antagonized with the 5-HT1B/1D receptor antagonist GR-127935. When the training doses of both flesinoxan and eltoprazine were administered concurrently, complete substitution for eltoprazine was obtained. We conclude that rats can learn to discriminate between two serotonergic drugs with overlapping stimulus properties and that the flesinoxan stimulus is mediated by 5-HT1A receptors and the eltoprazine stimulus, under these particular training conditions, by 5-HT1B receptors.