Life Sciences, Vol. 36, pp. 1233-1238 Pergamon Press Printed in the U.S.A. 1-METHYL-4-PHENYL-I,2,3,6-TETRAHYDROPYRIDINE (MPTP) DOES NOT DESTROY NIGROSTRIATAL NEURONS IN THE SCORBUTIC GUINEA PIG Thomas L. Perry 1, Voon Wee Yong, Masatoshi Ito, Karen Jenes, Richard A. Wall, James G. Foulks, James M. Wright, and Stephen J. Kish* Department of Pharmacology Therapeutics, University of British Columbia, Vancouver, Canada, V6T IW5; and Human Brain Laboratory*, Clarke Institute of Psychiatry, Toronto, Canada, M5T 1R8 (Received in final form January 22, 1984) Summary Guinea pigs were injected subcutaneously with 1-methyl-4- phenyl-l,2,3,6-tetrahydropyridine (MPTP) in maximal tolerated doses (8 mg/kg, once daily) for 10 or 15 days. No neurological effects were noted, other than sedation and hypotonia lasting a few hours after each injection, either in animals maintained on normal diet or in animals fed an ascorbate-deficient diet and rendered severely scorbutic. Subsequent chemical analyses of the striatum showed no evidence of lasting damage to nigrostriatal dopaminergic neurons in MPTPtreated guinea pigs on normal diet, and minimal evidence of per- manent damage to these neurons in scorbutic animals. MPTPwas un- detectable in the urine of MPTP-treated animals, although a meta- bolite, presumably 1-methyl-4-phenylpyridinium ion (MPP +) was reg- ularly present in urine. The relative lack of neurotoxicity of MPTP in the guinea pig remains unexplained. This species clearly is not a suitable small animal for MPTP-induced parkinsonism. The parenteral injection or inhalation of 1-methyl-4-phenyl-l,2,3,6- tetrahydropyridine (MPTP) has resulted in the development of severe and last- ing symptoms of Parkinson's disease in human subjects (1-3). Monkeys of 3 different species injected repeatedly with low doses of MPTP develop neuro- logical signs that closely resemble human Parkinson's disease, and their brains later show a striatal depletion of dopamine and a loss of neurons in the zona compacta of the substantia nigra (4-7). In the squirrel monkey, MPTP has been shown to be rapidly metabolized to 1-methyl-4-phenylpyridinium ion (MPP+), only the latter compound being detectable in brain one hour after systemic injection of MPTP (7). Until the recent demonstration that MPTP damages nigrostriatal dopaminer- gic neurons in mice (8,9), efforts to produce a model of Parkinson's disease in small laboratory rodents generally had been unsuccessful. A possible ex- ception was the reported 50 reduction of striatal dopamine in guinea pigs chronically treated with MPTP (10). IAddressee for reprints. 0024-3205/85 $3.00 + .00 Copyright (c) 1985 Pergamon Press Ltd.