CHRONIC ADMINISTRATION OF 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE TO MONKEYS - BEHAVIORAL, MORPHOLOGICAL AND BIOCHEMICAL CORRELATES

The behavioural, biochemical and morphological effects of a chronic ad ministration of low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrid ine (MPTP) were studied in the common marmoset. Monkeys received the t oxin (1 mg/kg i.p.) twice a week for four months. Group A monkeys were studied one week after the last injection of MPTP; group B monkeys we re studied eight months after the last toxic injection. The monkey beh aviour was observed throughout the experiment; the biochemical and mor phological correlates were studied post mortem in the neostriatum and in the substantia nigra, respectively. Data collected from MPTP-treate d marmosets were compared to those obtained from sham-injected control monkeys. The results can be summarized as follows. (1) In all MPTP-tr eated marmosets a progressive Parkinsonism occurred. In group B monkey s, a gradual behavioural recovery was observed after MPTP was disconti nued. (2) Biochemical analysis of group A marmosets showed a depletion of dopamine, of 3,4-hydroxyphenylacetic acid and of homovanillic acid , and no variations in dopamine turnover in the neostriatum of MPTP-tr eated marmosets. In group B, biochemical analysis showed no difference s between controls and MPTP-treated animals. (3) Morphological analysi s showed that the density of midbrain dopaminergic neurons located in the substantia nigra was unchanged in group A monkeys, but was reduced by 6.8% in MPTP-treated monkeys of group B. The measurement of cross- sectional area showed that midbrain dopaminergic neurons were swollen in MPTP-treated monkeys of group A, with a 11.0% increase of cell size as compared to controls. In group A the nuclei were also swollen, bei ng 304.8% larger in MPTP-treated monkeys, with a nucleus-to-cytoplasm ratio of 65.9% (as compared to 34.0% of controls). In group B monkeys cell size was increased by 18.4% in MPTP-treated marmosets, but the nu clei were of comparable size. The present data show that a chronic adm inistration of low doses of MPTP brings about biochemical and morpholo gical abnormalities. The first occur acutely in terminals and are reve rted early after discontinuance of exposure to the toxin; the latter o ccur in dopaminergic perikarya, last longer than biochemical abnormali ties and, at variance with them, increase in severity after MPTP is di scontinued. Morphological abnormalities include early events, such as a transient swelling of nuclei or a long-lasting swelling of neurons, and late events, such as a decrease in the number of tyrosine hydroxyl ase-positive perikarya. The different time course of events occurring in terminals and in the perikarya of midbrain dopaminergic neurons sug gests that the damage occurring in these two compartments is different in nature.