Chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to monkeys: behavioural, morphological and biochemical correlates.
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)
Albanese
A
A
Istituto di Neurologia, Università Cattolica del Sacro Cuore, Roma, Italy.
Granata
R
R
Gregori
B
B
Piccardi
M P
MP
Colosimo
C
C
Tonali
P
P
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002144:Callithrix; D004195:Disease Models, Animal; D004298:Dopamine / Q000032:analysis; D005133:Eye Movements / Q000187:drug effects; D005260:Female; D006719:Homovanillic Acid / Q000032:analysis; D020267:MPTP Poisoning; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000737:chemistry / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000032:analysis; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000473:pathology; D012720:Severity of Illness Index; D016037:Single-Blind Method; D013378:Substantia Nigra / Q000187:drug effects* / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis; D014828:Vocalization, Animal / Q000187:drug effects
D009419:Nerve Tissue Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid