To investigate the role of brain catecholamines in the development of spontaneous hypertension, rats were treated with different doses of the neurotoxins 6-hydroxydopamine (6-OHDA) or DSP-4 (N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine hydrochloride). Intracerebroventricular (i.c.v.) 6-OHDA attenuated the development of hypertension in spontaneously hypertensive rats (SHR) and also lowered the systolic blood pressure (BP) in Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Norepinephrine was markedly and dose-dependently depleted in brain areas of all three substrains. Dopamine was affected also, although to a lesser extent. Pretreatment with the norepinephrine-uptake inhibitor desmethylimipramine (DMI) did not influence the effect of 6-OHDA on the development of hypertension in SHR. DMI largely antagonized the 6-OHDA-induced depletion of brain norepinephrine, while dopamine depletion was not affected. Specific depletion of brain norepinephrine by treatment with DSP-4 did not alter the rise in BP in SHR. These results suggest that the effect of 6-OHDA on the development of hypertension in SHR may not be mediated through destruction of brain norepinephrine neurons, but that interruption of brain dopaminergic mechanisms is a possibility in this respect.