Studies were carried out in the rat to investigate whether serotonin (5-HT) is involved in the regulation of vasopressin (ADH) release. For this purpose plasma ADH levels were measured in rats treated with drugs enhancing 5-HT transmission, such as d-fenfluramine and quipazine and with 5-HT depleting drugs, p-chlorophenylalanine (PCPA) and 5,7-dihydroxytryptamine (5,7-DHT). Forebrain 5HT, noradrenaline (NA) and dopamine (DA) were also measured. d-Fenfluramine and quipazine induced dose-related increases in plasma ADH levels in normohydrated rats. The effects of quipazine and d-fenfluramine were prevented by PCPA, indicating that 5-HT transmission was required for the biologic response. 5,7-DHT and PCPA pretreatment decreased forebrain 5-HT content and prevented ADH increases involved by water deprivation, suggesting that 5HT is necessary for the hormonal response to osmotic stimuli. The results summarized imply that serotonin may have a role in the physiological release of ADH from neurohypophysis.