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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‐HT 2 antagonist WY‐50,324 in pigeons
Author(s) -
Barrett James E.,
Zhang Lei
Publication year - 1991
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430240205
Subject(s) - buspirone , agonist , 8 oh dpat , 5 ht1a receptor , 5 ht1 receptor , chemistry , pharmacology , antagonist , 5 ht receptor , serotonin , 5 ht2 receptor , medicine , endocrinology , receptor
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‐HT 2 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‐HT 2 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.