Catecholamine uptake sites: characterization, localization, and a role in the production of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism

Dopamine and norepinephrine are inactivated by specific high affinity transport systems which mediate the recapture of the amines into presynaptic nerve terminals. [3H]Maxindol labels neuronal dopamine uptake sites in corpus striatum membranes and neuronal norepinephrine uptake sites in cerebral cortex and submaxillary/sublingual gland membranes. The potencies of various inhibitors of biogenic amine uptake in reducing [3H]mazindol binding in striatal membranes correlate with their potencies for inhibition of neurona [3H]dopamine accumulation, whereas their potencies in reducing [3H]mazindol binding to cortical and salivary gland membranes correlate with their potencies for inhibition of neuronal [3H]norepinephrine accumulation. The association of [3H]mazindol binding sites with neuronal dopamine uptake sites in the corpus striatum is further supported by the reduction of [3H]mazindol binding sites in striatal membranes following destruction of dopaminergic neurons by 6-hydroxydopamine. Similarly, destruction of noradrenergic neurons by N-(2-chloro-ethyl)-N-ethyl-2-bromobenzylamine(DSP-4) decreases [3H]mazindol binding to cortical membranes. Dopamine and norepinephrine uptake sites in rat brain have been differentially visualized using [3H]mazindol autoradiography. N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces neuropathologic and clinical abnormalities in humans and animals that closely resemble idiopathic Parkinson disease. [3H]MPTP binds with high affinity to brain membranes. The chemical specificity of the binding sites corresponds to structure-activity requirements for neurotoxicity