Acute Effects of 1‐Methyl‐4‐Phenyl‐1, 2, 3, 6‐Tetrahydropyridine in a Model of Rat Designated a Poor Metabolizer of Debrisoquine

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Abstract
The relationship between oxidative polymorphisms and the cause of Parkinson's disease is controversial. The drug l‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP), which induces parkinsonism in humans and in some animal models, is metabolized by cytochrome P450 db1 isozyme (the same enzymatic system implicated in 4‐hydroxylation of debrisoquine). In this study, we treated females of three rat species, which differ in their ability to hydroxylate debrisoquine, with MPTP (three doses of 30 mg/kg s.c. at 12‐h intervals), and we measured their motor activity and brain monoamine levels. Female dark‐adapted rats (poor metabolizers of debrisoquine) showed a more pronounced and more maintained reduction of their motor activity after treatment with MPTP. MPTP‐treated, dark‐adapted rats also had a depletion of noradrenaline in the diencephalon and a depletion of dopamine and serotonine and their respective metabolites in the limbic system when compared with the other two species. These results suggest that oxidative polymorphism of debrisoquine plays a role in the acute effects of MPTP.