WAY-100635 inhibits 8-OH-DPAT-stimulated oxytocin, ACTH and corticosterone, but not prolactin secretion

Previous studies suggest that the 5-HT(1A) receptor agonist 8-hydroxy- 2-(di-n-propylamino) tetralin (8-OH-DPAT) increases the secretion of oxytocin, adrenocorticotropic hormone (ACTH), corticosterone and prolactin but not renin. However, the lack of selective 5-HT(1A) receptor antagonists made it difficult to confirm that 5-HT(1A) receptors mediate the neuroendocrine responses to 8-OH-DPAT. This study investigated the effects of increasing doses of a selective 5-HT(1A) receptor antagonist, N-[2-[4-(2- methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY-100635) on neuroendocrine responses induced by the 5-HT(1A) receptor agonist 8-OH-DPAT in adult male rats. 8-OH-DPAT, 500 μg/kg s.c., increased plasma levels of oxytocin (to 970% above basal levels); ACTH (to 1622% above basal levels), corticosterone (to 458% above basal levels) and prolactin (to 313% above basal levels), but not renin. The lowest 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 corticosterone levels. At a dose of 1 mg/kg (s.c.), WAY-100635 completely blocked the oxytocin and ACTH responses and maximally inhibited the corticosterone response to 8-OH-DPAT, although corticosterone levels were still above basal. In contrast, the increase in prolactin secretion, induced 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 were markedly elevated (1550%) and administration of 8-OH-DPAT significantly elevated plasma renin concentration. Taken together, these data indicate that: (1) 8-OH-DPAT stimulates oxytocin, ACTH, and corticosterone but not prolactin secretion via activation of 5-HT(1A) receptors and (2) blockade of 5-HT(1A) receptors may unmask 8-OH-DPAT simulation of renin secretion via non-5-HT(1A) receptor mechanisms.