1-Methyl-4-phenylpyridine (MPP+): regional dopamine neuron uptake, toxicity, and novel rotational behavior following dopamine receptor proliferation.

The regional uptake and subsequent dopaminergic toxicity, receptor proliferation, and rotational behavior pharmacology following intracerebral 1-methyl-4-phenylpyridine (MPP+) administration was determined in the rat. [3H]MPP+ was transported by the high-affinity dopamine uptake system equally in the caudate-putamen (CP), nucleus accumbens (NA) and olfactory tubercle (OT), and to a lesser extent in the substantia nigra. Consistent with the equivalent uptake of [3H]MPP+ by mesostriatal and mesolimbic dopamine neurons, dopamine concentrations of the ipsilateral CP and NA were decreased equally (83-98%) following a 10, 17.5 or 25 microgram injection of MPP+ along the left medial forebrain bundle (MFB). At four weeks after a 25 microgram injection of MPP+ into the MFB, the concentration (Bmax) of D2 receptors in the left CP was increased by 42% compared with the intact hemisphere. D2 receptors did not proliferate in the denervated nucleus accumbens. The affinity (Kd) of D2 receptors was not affected in either the CP or NA. The MPP+ injection, which was restricted to the region of striatonigral efferent fibers, also produced a 60% decrease in the GABA content of the substantia nigra. Ipsiversive rotational behavior was induced in MPP+-treated rats by systemic injections of d-amphetamine. Systemic injections of neither the dopamine agonist apomorphine nor agonist prodrug formulation of 1-DOPA and carbidopa induced contraversive rotation. These behavioral and neurochemical results are identical to those observed following concomitant destruction of striatonigral GABA and mesostriatal dopamine projections, and indicate that MPP+ may be toxic to GABAergic as well as to A10 and A9 dopaminergic neurons.