The mechanisms of the cardiovascular effects of i.c.v. administered thyrotropin-releasing hormone (TRH) were studied in anesthetized rats. The pressor response to TRH was blocked after depletion of catecholamines by i.p. reserpine whereas vagotomy or i.v. methylatropine reduced the TRH-induced tachycardia. Centrally administered catecholaminergic or cholinergic receptor antagonists failed to block the cardiovascular effects of TRH. However, centrally administered reserpine reduced the pressor response to TRH and the affinity of its specific binding in brain homogenates. Similar reduction in the affinity of TRH binding was observed after depletion of brain serotonin with p-chlorophenylalanine (PCPA), which was earlier shown to antagonize the TRH-induced pressor effect. It was concluded that TRH acts through a central mechanism to enhance the sympathetic outflow and to attenuate the vagal cardiac activity which leads to hypertension and tachycardia. Central serotonergic mechanisms rather than those related to catecholamines appear to be involved in the pressor response to TRH.