Neuroendocrine profile of the potential anxiolytic drug S-20499.
The neuroendocrine profile of the serotonin 5-HT1A 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-HT1A 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-HT1A receptors, although activation of dopamine D2 receptors may contribute to these responses. Like other 5-HT1A 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.
Levy
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Department of Pharmacology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153, USA.
Li
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Gustafson
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Van de Kar
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LD
D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003345:Corticosterone / Q000097:blood*; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008297:Male; D009490:Neurosecretory Systems / Q000187:drug effects* / Q000502:physiology; D010869:Pindolol / Q000008:administration & dosage / Q000494:pharmacology; D011388:Prolactin / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D013134:Spiperone / Q000008:administration & dosage / Q000494:pharmacology; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D013237:Stereoisomerism
D014151:Anti-Anxiety Agents; D018491:Dopamine Agonists; D017366:Serotonin Receptor Agonists; D013141:Spiro Compounds; C075319:alnespirone; D013134:Spiperone; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D010869:Pindolol; D012083:Renin; D003345:Corticosterone