Differential Interaction of 1-Methyl-4-Phenylpyridinium Ion with the Putatively Vesicular Binding Site of [3H]Tyramine in Dopaminergic and Nondopaminergic Brain Regions

Abstract: The neurotoxin 1-methyl-4-phenylpyridinium ion (MPP⁺) in the brain striatum has recently been shown to bind at a putatively vesicular site labeled by [³H]tyramine ([³H]TY). Whereas in the rat and mouse striatum MPP⁺ antagonized TY binding competitively, in the cerebellum there was a mixed-type antagonism, which suggests the simultaneous occupancy of two different sites. K _i values from displacement curves revealed a fourfold difference in the affinity of MPP⁺ for TY sites in the two brain regions. The degeneration of central noradrenergic terminals induced by an intraperitoneal injection of the toxin N -(2-chloroethyl)- N -ethyl-2-bromobenzylamine in rats decreased by 80% the maximal number of cerebellar TY binding sites, while not affecting striatal binding. Furthermore, guanethidine, a marker for noradrenaline (NA) vesicles, potently inhibited TY binding in NA-innervated regions, such as the cerebellum and the parietal cortex, and poorly in the striatum. It is concluded (a) that both MPP⁺ and TY may also label NA vesicles and (b) that the vesicular carriers for dopamine and NA have different characteristics, which may underlie a regional specificity in the rate of endovesicular sequestration of MPP⁺, with either neurodegenerative or neuroprotective consequences, depending on the brain area involved.