MPP+ (1-methyl-4-phenylpyridinium) mimicked MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in producing marked, dose-related depletion of cardiac norepinephrine after a single oral or subcutaneous dose in mice. MPP+ was approximately 4-fold more potent than MPTP in depleting norepinephrine, but the onset of depletion was not faster for MPP+ than for MPTP. The time courses of the effects of both compounds were similar to that for 6-hydroxydopamine, with maximum depletion occurring at 1 day, partial recovery at 2 and 4 days, and full recovery of norepinephrine concentrations at 1 week. Desipramine, over a dose range that completely prevented the depletion of cardiac norepinephrine by 6-hydroxydopamine at 24 hr, did not prevent cardiac norepinephrine depletion by either MPP+ or MPTP. In a short duration experiment, one or two doses of desipramine also failed to prevent heart norepinephrine depletion by MPP+ or by MPTP, although a slight antagonism was found. EXP 561 (4-phenylbicyclo[2,2,2]octan-1-amine hydrochloride monohydrate), another uptake inhibitor with possibly longer duration of action, also did not protect against norepinephrine depletion by a single dose of MPP+ or MPTP at a dose that prevented norepinephrine depletion by 6-hydroxydopamine. In mice given four daily doses of MPTP, EXP 561 prevented the depletion of norepinephrine in the frontal cortex and of dopamine in the striatum but not the depletion of norepinephrine in heart or spleen. Thus, both MPTP and MPP+ deplete norepinephrine in mouse heart, and this effect of the two compounds is resistant to antagonism by uptake inhibitors that antagonize the effects of MPTP on brain catecholamines.