1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the rat: characterization and age-dependent effects

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent dopaminergic toxin that has been found to produce Parkinson's disease-like symptoms in humans and monkeys. The neurotoxic effects of MPTP appear to be reduced in rodents where multiple dosing procedures are required to demonstrate long-lasting neuronal deficits. In the present study, the neurotoxic effects of MPTP were further characterized in the rat. Following the repeated administration of MPTP, pronounced (60-80%) and dose-dependent depletions of striatal dopamine and serotonin concentrations were found in the rat brain. Time-course studies revealed that while striatal dopamine concentrations remained consistently reduced for at least 8 weeks following MPTP treatment, striatal serotonin depletions as well as MPTP-induced monoamine depletions in other brain regions were transient in nature. Pretreatment with the MAO-B inhibitor pargyline afforded a selective and complete protection of striatal dopamine levels without significantly affecting MPTP-induced striatal serotonin depletions. Similarly, treatment with ascorbic acid was found to selectively attenuate MPTP-induced dopamine depletions in rats. The neurotoxic effects of MPTP were also found to increase in the developing rat. No significant brain monoamine depletions were observed in neonatal rats following the repeated administration of MPTP. However, MPTP-induced neurotoxicity progressively increased in older rats. The present results indicate that when appropriate treatment procedures are used, a pronounced, selective, age-dependent, and long-lasting MPTP-induced reduction in striatal dopamine concentrations can be observed in the rat brain. The present results are discussed in reference to the putative mechanisms and species differences of MPTP-induced neurotoxicity.