Neurochem. Int. Vol. 11, No. 4, pp. 379-381, 1987 0197-0186/87 $3.00 + 0.00 Printed in Great Britain. All fights res©rved © 1987 Pergamon Journals Ltd CRITIQUE MPTP INDUCED DOPAMINERGIC NEUROTOXICITY-- A USEFUL MODEL IN THE STUDY OF PARKINSON'S DISEASE? P. RIEDERER*~" and M. B. H. YOUDIM~ *Clinical Neurochemistry Department, University of Wiirzburg, Wiirzburg, F.R.G. and :~Rappaport Family Research Institute and Department of Pharmacology, Technion, Haifa, Israel The article by Kinemuchi et al. (1987) on "the neurotoxicity of 1-methyl-4-phenyl-l,2,3,6-tetra- hydropyridine (MPTP) and its relevance to Parkin- son's disease" (PD) is a comprehensive review of what is known about mechanism of action of this neurotoxin and its relation to the pathogenesis of PD. Although MPTP induced Parkinsonism at first glance appears to be a good model for PD, it may be more suitable for akinesia and rigidity, while resting tremor is a symptom that is rarely seen (Ballard et al., 1985). Thus, the MPTP model in primates reflects symptoms of the rigidity akinesia-type of PD and less of the equivalent type of the disease in man where rigidity, akinesia and tremor are seen. Acute neu- rotoxicity with MPTP causes certain irreversible damage of substantia nigra (SN) pars compacta neurons in monkeys, but does not trigger a progressive and time independent loss of neurons. In fact, there is evidence for a recovery of serotonin and noradrenaline metabolites in the CSF of MPTP treated monkeys after a relatively short period. How- ever, homovanillic acid remains low (Burns et al., 1983). MPTP is unable to produce resting tremor in rodents and frequently also in monkeys except Rhesus. This phenomenon might be related to the pure lesion of SN in acute and subacute action of the neurotoxin. Tremor, according to Struppler et al. (1976), Poirier et al. 0976) and Marsden (1984) occurs only after multisystem degeneration. In line with such studies is the biochemical as well as the pharmacological evidence, which demonstrates a multitransmitter involvement in the pathogenesis of fAddress correspondence to: Professor P. Riederer, Clinical Neurochemistry, Department of Psychiatry, University of Wiirzburg, Fiichsleinstr. 15, 8700 Wfirzburg, F.R.G. tremor. Serotonergic, noradrenergic, dopaminergic, cholinergic and GABAergic systems seem to be in- volved (Auff et al., 1987). A major difference between PD and MPTP- parkinsonism is the fact that monkeys treated with MPTP frequently stop eating and drinking, a phe- nomenon that might explain some of the behavior of these animals (Przuntek, personal communication). In PD, eating and drinking disorders are not of major importance and only rarely is it observed. Phases of excessive food intake or lack of it belong to very rare conditions (Birkmayer and Riederer, 1983). A further contradiction between idiopathic PD and MPTP-Iike parkinsonism can be found in the degen- eration of striatal subareas. In PD the putamen shows greater denervation than the caudate nucleus (Bernheimer et al., 1973). In contrast, highest binding capacity of [3H]MPTP has been noted for the caudate nucleus (Javitch et al., 1984; Parsons and Rainbow, 1984). By all accounts, this would imply the motor loop (motor-, premotor cortex input to putamen; putamen-globus pallidus-thalamus-motor cortex) is less likely to be involved than the behavioral regu- lation via the loop which drives the caudate nucleus via the afferents from the association cortex (psycho- motor behavior). Kinemuchi and co-authors (this volume, pp. 359-373) have given a detailed description of the mechanism of MPTP-toxicity, but no definite conclu- sions can be reached at this time. The extreme vulnerability of SN to this neurotoxin favors the suggestion of biochemical abnormalities in this brain area (Table 1). In this context, the localization and function of monoamine oxidase (MAO) (the enzyme which generates hydrogen peroxide and aldehydes in glia, cell bodies and fibres) is important. This enzyme has a key role because of its unique differentiation 379