Neuroendocrine profile of the potential anxiolytic drug S-20499

The neuroendocrine profile of the serotonin 5-HT_1A receptor agonist and potential anxiolytic drug (+)-4[N-(5-methoxy-chroman-3-yl]N-propylamino]butyl-8-azaspiro-(4, 5)-decane-7,9-dione (S-20499) was examined in conscious male rats. S-20499 (0.01-20 mg/kg i.p.) dose-dependently elevated plasma adrenocorticotropin (ACTH) and corticosterone concentrations, with maximal effects observed at 15-30 and 30-60 min respectively. S-20499 also reduced plasma prolactin concentration, and did not alter plasma renin activity. S-20499 (1 mg/kg i.p.) also reduced blood pressure and heart rate within 10 min, suggesting reduced sympathetic output. Pretreatment with the 5-HT_1A0 receptor antagonists (-)-pindolol (0.3 mg/kg i.p.) or spiperone (0.01 or 3 mg/kg s.c.) significantly attenuated the stimulatory effects of S-20499 on plasma ACTH and/or corticosterone concentrations. The data suggest that S-20499 stimulates the hypothalamic-pituitary adrenal axis by activating 5-HT_1A receptors, although activation of dopamine D₂ receptors may contribute to these responses. Like other 5-HT_1A receptor agonists, S-20499 does not increase renin secretion. Additionally, it reduces prolactin secretion, presumably by acting as a weak dopamine D₂ receptor agonist in the pituitary.