Antidepressant-like activity of compounds with varying efficacy at 5-HT_1A receptors

Three novel compounds (WY-48,723, WY-50,324, WY-47,846 [zalospirone]), with high affinity but varying efficacy for the 5-HT_1A receptor, were examined for producing the 5-HT behavioral syndrome and for potential antidepressant activity in the forced swimming test (FST). WY-50,324 was more potent than WY-48,723 at producing the 5-HT syndrome, but unlike WY-48,723, it produced only some of the behaviors of the 5-HT syndrome and its profile resembles that of a partial agonist. WY-48,723 appeared to be a full agonist because it produced behavioral effects similar to those of 8-OH-DPAT. The syndrome produced by these compounds was antagonized by pretreatment with pindolol. Zalospirone did not produce the syndrome but it antagonized the syndrome produced by 8-OH-DPAT. WY-48,723 and WY-50,324 reduced immobility time in the FST. These effects were similar to those produced by the tricyclic antidepressant desipramine and the 5-HT_1A agonist 8-OH-DPAT. Zalospirone did not reduce immobility time, but increased it, which made it difficult to evaluate in this screen. These results suggest that the full agonist WY-48,723 and the partial agonist WY-50,324 may both possess antidepressant activity. Antidepressant-like activity appears to be a characteristic of compounds with a medium to high efficacy for activating 5-HT_1A receptors.