Chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to monkeys: behavioural, morphological and biochemical correlates

Neuroscience. 1993 Aug;55(3):823-32. doi: 10.1016/0306-4522(93)90444-k.

Abstract

The behavioural, biochemical and morphological effects of a chronic administration of low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were studied in the common marmoset. Monkeys received the toxin (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 were studied eight months after the last toxic injection. The monkey behaviour was observed throughout the experiment; the biochemical and morphological correlates were studied post mortem in the neostriatum and in the substantia nigra, respectively. Data collected from MPTP-treated marmosets were compared to those obtained from sham-injected control monkeys. The results can be summarized as follows. (1) In all MPTP-treated marmosets a progressive Parkinsonism occurred. In group B monkeys, a gradual behavioural recovery was observed after MPTP was discontinued. (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-treated marmosets. In group B, biochemical analysis showed no differences between controls and MPTP-treated animals. (3) Morphological analysis 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, being 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 nuclei were of comparable size. The present data show that a chronic administration of low doses of MPTP brings about biochemical and morphological abnormalities. The first occur acutely in terminals and are reverted early after discontinuance of exposure to the toxin; the latter occur in dopaminergic perikarya, last longer than biochemical abnormalities and, at variance with them, increase in severity after MPTP is discontinued. 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 hydroxylase-positive perikarya.(ABSTRACT TRUNCATED AT 400 WORDS)

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / administration & dosage*
  • 3,4-Dihydroxyphenylacetic Acid / analysis
  • Animals
  • Behavior, Animal / drug effects*
  • Callithrix
  • Disease Models, Animal
  • Dopamine / analysis
  • Eye Movements / drug effects
  • Female
  • Homovanillic Acid / analysis
  • MPTP Poisoning
  • Male
  • Motor Activity / drug effects
  • Neostriatum / chemistry
  • Neostriatum / drug effects*
  • Nerve Tissue Proteins / analysis
  • Neurons / enzymology
  • Neurons / pathology
  • Parkinson Disease, Secondary / chemically induced*
  • Parkinson Disease, Secondary / pathology
  • Severity of Illness Index
  • Single-Blind Method
  • Substantia Nigra / drug effects*
  • Substantia Nigra / pathology
  • Tyrosine 3-Monooxygenase / analysis
  • Vocalization, Animal / drug effects

Substances

  • Nerve Tissue Proteins
  • 3,4-Dihydroxyphenylacetic Acid
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Tyrosine 3-Monooxygenase
  • Dopamine
  • Homovanillic Acid