THE HIGH-SENSITIVITY TO ROTENONE OF STRIATAL DOPAMINE UPTAKE SUGGESTSTHE EXISTENCE OF A CONSTITUTIVE METABOLIC DEFICIENCY IN DOPAMINERGIC-NEURONS FROM THE SUBSTANTIA-NIGRA

The toxicity of the 1-methyl-4-phenylpyridinium ion (MPP+), an inhibit or of complex I of the respiratory chain, on nigrostriatal dopaminergi c neurons contrasts with its relative inefficiency towards other catec holaminergic cell populations in spite of their ability to accumulate this neurotoxin through their high-affinity uptake system. A constitut ive metabolic deficiency of the nigrostriatal dopaminergic neurons cou ld account for their particular vulnerability to MPP+. In order to sub stantiate this hypothesis, we compared the inhibitory effects of roten one, an inhibitor of mitochondrial oxidative phosphorylation, on the u ptake of dopamine, serotonin, noradrenaline and GABA in mouse striatal synaptosomes, and of dopamine, serotonin and GABA in cultured mesence phalic neurons. In both preparations, the uptake of dopamine was much more affected than that of other neurotransmitters by rotenone. This r esult was confirmed using two other unrelated inhibitors of oxidative phosphorylation. Moreover, dopamine uptake in synaptosomes from the do rsolateral striatum was more sensitive to rotenone than uptake in syna ptosomes from the nucleus accumbens. This indicates that intrinsic met abolic properties of the nigrostriatal dopaminergic neurons may explai n the strong inhibition by rotenone of striatal dopamine uptake. Altog ether, these results suggest that a constitutive metabolic deficiency could account, at least in part, for the selective vulnerability of th e nigrostriatal dopaminergic pathway to the action of the neurotoxin M PP+.