The effect of the serotonin-releasing drug parachloroamphetamine (PCA) on plasma renin activity was studied in rats 4 days after surgical lesions of the mediobasal hypothalamus, anterolateral deafferentation of the mediobasal hypothalamus, posterolateral deafferentation, or hypophysectomy. PCA increased plasma renin activity in sham-operated rats, but it failed to increase plasma renin activity in rats with mediobasal hypothalamic lesions or posterolateral deafferentation. The response to PCA was unaffected by anterolateral deafferentation and enhanced by hypophysectomy. There were no significant differences in plasma renin activity in lesioned, deafferented, and hypophysectomized rats injected with saline. The data indicate that the mediobasal hypothalamus is part of the pathway by which central serotonergic neurons affect renin secretion, and that the effect is not mediated via hormones of the pituitary gland.