The loss of dopaminergic neurons in Parkinson's disease is associated with a glial reaction and the overproduction of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha). TNF-alpha acts via two different receptors, TNFR1 and TNFR2, and is believed to have both a neuroprotective and a deleterious role for neurons. In order to analyze the putative role of TNF-alpha in parkinsonism, we compared the effect of the parkinsonian drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice lacking TNFR1, TNFR2, or both receptors and in wild-type littermates. We show that MPTP does not affect spontaneous activity or anxiety in any of the groups and that it reduces motor activity on a rotarod in double knock out mice but not in mice lacking only one receptor. Postmortem analysis revealed no differences in the number of nigral dopaminergic neurons whatever the group. In contrast, striatal dopamine level was slightly decreased in double knock-out mice and more reduced by MPTP in this group than in the other groups of mice. In addition, dopamine turnover was significantly more increased in double knock out mice after MPTP injection. These data suggest that TNF-alpha does not participate in the death of dopaminergic neurons in parkinsonism but that it slightly alters dopamine metabolism or the survival of dopaminergic terminals by a mechanism involving both receptors.