The High Sensitivity to Rotenone of Striatal Dopamine Uptake Suggests the Existence of a Constitutive Metabolic Deficiency in Dopaminergic Neurons From the Substantia Nigra

The toxicity of the 1-methyl-4-phenylpyridinium ion (MPP⁺), an inhibitor of complex I of the respiratory chain, on nigrostriatal dopaminergic neurons contrasts with its relative inefficiency towards other catecholaminergic cell populations in spite of their ability to accumulate this neurotoxin through their high-affinity uptake system. A constitutive metabolic deficiency of the nigrostriatal dopaminergic neurons could account for their particular vulnerability to MPP⁺. In order to substantiate this hypothesis, we compared the inhibitory effects of rotenone, an inhibitor of mitochondrial oxidative phosphorylation, on the uptake of dopamine, serotonin, noradrenaline and GABA in mouse striatal synaptosomes, and of dopamine, serotonin and GABA in cultured mesencephalic neurons. In both preparations, the uptake of dopamine was much more affected than that of other neurotransmitters by rotenone. This result was confirmed using two other unrelated inhibitors of oxidative phosphorylation. Moreover, dopamine uptake in synaptosomes from the dorsolateral striatum was more sensitive to rotenone than uptake in synaptosomes from the nucleus accumbens. This indicates that intrinsic metabolic properties of the nigrostriatal dopaminergic neurons may explain the strong inhibition by rotenone of striatal dopamine uptake. Altogether, these results suggest that a constitutive metabolic deficiency could account, at least in part, for the selective vulnerability of the nigrostriatal dopaminergic pathway to the action of the neurotoxin MPP⁺.