A comparison of the oxytocin and vasopressin responses to the 5-HT(1A) agonist and potential anxiolytic drug alnespirone (S-20499)

The effect of the serotonin(1A) (5-HT(1A)) agonist alnespirone (S- 20499) on the secretion of both oxytocin and vasopressin was examined in the same conscious, unrestrained male rats. The dose-response and time-course effects on the secretion of oxytocin and vasopressin revealed that alnespirone stimulated oxytocin in a dose-dependent manner, but did not increase vasopressin secretion. Time of maximal effect following injection of alnespirone (5 mg/kg, IP) was as early as 15 min postinjection, with significant stimulation persisting for 30 min. Pretreatment with a low dose of the 5-HT(1A)/β-adrenoceptor antagonist (-)-pindolol (0.3 mg/kg, SC), 30 min prior to injection of alnespirone (0, 2, 5, and 10 mg/kg, IP) shifted the dose-response curve to the right and inhibited the effect of alnespirone on plasma oxytocin concentration. Furthermore, pretreatment with a low or a high dose of the 5-HT(1A/2A)/dopamine D₂ antagonist spiperone (0.01 or 3 mg/kg, SC) dose dependently shifted the alnespirone dose-response curve effect of alnespirone to the right. None of these drugs, alone or in combination, altered plasma vasopressin levels. These studies suggest that 5-HT(1A) receptor mechanisms mediate the effect of alnespirone on the secretion of oxytocin. Furthermore, these studies suggest that 5-HT(1A) receptor mechanisms do not participate in the serotonergic regulation of vasopressin secretion.