WAY-100635 INHIBITS 8-OH-DPAT-STIMULATED OXYTOCIN, ACTH AND CORTICOSTERONE, BUT NOT PROLACTIN SECRETION

Previous studies suggest that the 5-HT1A receptor agonist 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT) increases the secretion of oxy tocin, adrenocorticotropic hormone (ACTH), corticosterone and prolacti n but not renin. However, the lack of selective 5-HT1A receptor antago nists made it difficult to confirm that 5-HT1A receptors mediate the n euroendocrine responses to 8-OH-DPAT. This study investigated the effe cts of increasing doses of a selective 5-HT1A receptor antagonist, eth oxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY-100635) on neuroendocrine responses induced by the 5-HT1A recept or agonist 8-OH-DPAT in adult male rats. 8-OH-DPAT, 500 mu g/kg s.c., increased plasma levels of oxytocin (to 970% above basal levels); ACTH (to 1622% above basal levels), corticosterone (to 458% above basal le vels) and prolactin (to 313% above basal levels), but not renin. The l owest dose of WAY-100635 (0.1 mg/kg s.c.) significantly inhibited the 8-OH-DPAT-induced increase in plasma oxytocin but not ACTH or corticos terone levels. At a dose of 1 mg/kg (s.c.), WAY-100635 completely bloc ked the oxytocin and ACTH responses and maximally inhibited the cortic osterone response to 8-OH-DPAT, although corticosterone levels were st ill above basal. In contrast, the increase in prolactin secretion, ind uced by 8-OH-DPAT was not inhibited by any dose of WAY-100635. At the highest dose of WAY-100635 (10 mg/kg, s.c.), basal prolactin levels we re markedly elevated (1550%) and administration of 8-OH-DPAT significa ntly elevated plasma renin concentration. Taken together, these data i ndicate that: (1) 8-OH-DPAT stimulates oxytocin, ACTH, and corticoster one but not prolactin secretion via activation of 5-HT1A receptors and (2) blockade of 5-HT1A receptors may unmask 8-OH-DPAT simulation of r enin secretion via non-5-HT1A receptor mechanisms. (C) 1998 Elsevier S cience B.V.