Anticonflict and discriminative stimulus effects of the 5‐HT_1A compounds WY‐47,846 and WY‐48,723 and the mixed 5‐HT_1A agonist/5‐HT₂ antagonist WY‐50,324 in pigeons

The effects of the pyrimidinylpiperazinyl imide WY‐47,846 (zalospirone), the substituted arylpiperazine WY‐48,723, and the adamantyl piperazine derivative WY‐50,324 were studied under punishment (conflict) procedures with pigeons to evaluate potential anxiolytic activity. These compounds were also studied in pigeons trained to discriminate administration of the serotonin (5‐HT)_1A agonist 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin [8‐OH‐DPAT] (0.3 mg/kg) or buspirone (1.0 mg/kg), both administered i.m., from saline. All three compounds have high affinity for the 5‐HT_1A receptor site and WY‐50,324 also has high affinity for 5‐HT₂ receptors, with activity as an antagonist at this site. Increases in punished responding occurred with all three drugs, with the magnitude of the increases in the order WY‐50,324 > WY‐48,723; > WY‐48,846; increases with WY‐50,324 reached almost 15,000% of control levels. Increases in punished responding occurred at doses that did not affect unpunished responding. Doses producing maximal effects of the three drugs were comparable (1.0 mg/kg), although WY‐48,723 and WY‐50,324 also produced large increases at doses as low as 0.1 mg/kg. All three drugs also substituted for 8‐OH‐DPAT and buspirone, with WY‐48,723 and WY‐50,324 producing complete substitution at 0.1–0.3 mg/kg, whereas WY‐47,846 did not substitute in 8‐OD‐DPAT‐trained pigeons until a dose of 10 mg/kg; in pigeons trained with buspirone, a dose of 1.0 mg/kg WY‐47,846 resulted in complete substitution. All three drugs appear to have potential anxiolytic and/or antidepressant activity through actions mediated at the 5‐HT_1A receptor. The unique combination of 5‐HT_1A agonist activity with 5‐HT₂ antagonist activity appears to confer potent anxiolytic‐like actions on WY‐50,324 that prompt additional exploration of the interactions between these receptor subtypes and their role in anxiety and other disorders.