DAMAGE TO DOPAMINERGIC NERVE-TERMINALS IN MICE BY COMBINED TREATMENT OF INTRASTRIATAL MALONATE WITH SYSTEMIC METHAMPHETAMINE OR MPTP

The mechanisms involved in methamphetamine (METH)-induced damage to ni grostriatal dopaminergic neurons in experimental animals are unknown. We have examined the possibility that perturbations in energy metaboli sm contribute to METH-induced toxicity by investigating the effects of systemic METH treatment in mice which received a unilateral intrastri atal infusion of malonate, a metabolic inhibitor which decreases ATP l evels. Malonate (1-4 mu mol) produced a dose-dependent decrease in str iatal dopamine (DA). The combined treatment of intrastriatal malonate with systemic METH resulted in greater damage to dopaminergic neurons than by METH or malonate treatment alone. In parallel studies, MPTP wa s administered to mice which received intrastriatal infusions of salin e or malonate. Similar to results obtained with METH, decreases in str iatal DA content and tyrosine hydroxlase (TH) activity were greatest i n MPTP-treated mice infused with malonate. The present results lend cr edence to the hypothesis that METH-induced increases in energy utiliza tion create a state of metabolic stress for DA neurons which may ultim ately contribute to the neurodegenerative effects of METH. Moreover, t he finding that combined malonate and MPTP treatment produced greater damage than either substance alone is consistent with the hypothesis t hat perturbations in energy metabolism contribute to the neuronal deat h produced by MPP(+).