ANTICONFLICT AND DISCRIMINATIVE STIMULUS EFFECTS OF THE 5-HT1A COMPOUNDS WY-47,846 AND WY-48,723 AND THE MIXED 5-HT1A 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-HT1A 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-47,846; 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-OH-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-HT1A receptor. The unique combination of 5-HT1A 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.