The aims of the study were to determine; (1) whether activation of serotonin (5-HT) receptors in the brain increases renin secretion, and (2) whether the hypertensive effects of a 5-HT agonist and 5-HT releaser obscure their ability to stimulate renin release. Various drugs that increase serotonergic neuro-transmission can activate the secretion of renin from the kidneys. Many of these drugs can also elevate blood pressure. Changes in blood pressure can alter renin secretion by activating renal baroreceptor mechanisms, so that a decrease in perfusion pressure will increase renin secretion and vice versa. To address the first objective, the 5-HT agonist RU 24969 (0, 10, 100 and 200 micrograms/kg) and the 5-HT releaser p-chloroamphetamine (0, 50, 500 and 1,000 micrograms/kg) were injected intracerebroventricularly (ICV) at doses lower than those that are peripherally effective. ICV injection of RU 24969 dose-dependently increased plasma levels of renin. ICV injection of the 5-HT2A/5-HT2C antagonist LY53857 (50 micrograms/kg) inhibited the renin response to peripherally injected RU 24969 (0, 1, 5 and 10 mg/kg i.p.), suggesting that 5-HT2A/5-HT2C receptors in the brain mediate the effect of peripherally injected RU 24969 on renin secretion. In contrast, ICV injection of p-chloroamphetamine decreased renin secretion. To determine whether hypertensive actions could account for the differences between RU 24969 and p-chloroamphetamine, we measured the effects of both p-chloroamphetamine and RU 24969 on blood pressure and heart rate. ICV injection of p-chloroamphetamine (1,000 micrograms/kg) produced a large rise of 44 mm Hg at 2 min and 25 mm Hg at 5 min after injection, while ICV injection of RU 24969 (200 micrograms/kg) caused a slower and smaller blood pressure elevation of 18 mm Hg at 5 min after injection. To determine whether the hypertensive effects of both RU 24969 and p-chloroamphetamine could mask their effects on renin secretion, rats were pretreated with the alpha 1 antagonist prazosin. Administration of prazosin (1 mg/kg s.c.), which prevents the hypertensive effects of p-chloroamphetamine, exposed a stimulatory effect of ICV-injected p-chloroamphetamine (500 micrograms/kg) on renin secretion and potentiated the effect of RU 24969 (5 mg/kg i.p.) on renin release. In conclusion, these data suggest that both RU 24969 and p-chloroamphetamine increase renin secretion through central 5-HT receptors, and that these effects are partially obscured by their hypertensive actions.