Structural and neurochemical effects in mouse cerebellum following neonatal methylazoxymethanol and 6-hydroxydopamine treatment.
The effects of neonatal treatment with the antimitotic agent methylazoxymethanol and the catecholamine neurotoxin 6-hydroxydopamine on cerebellar morphology and monoamine innervation in the N.M.R.I. mouse has been studied. Methylazoxymethanol (25 mg/kg s.c.) treatment induced a cerebellar weight reduction of 40% as observed in the adult stage, while other CNS regions analysed were unaffected. An obvious atrophy of the cerebellar cortex was found, with an irregular distribution of the Purkinje cells, while Bergmann glia fibers deviated from their normal radial configuration and showed a tendency to form clusters. A 65% increase of tyrosine hydroxylase immunoreactive fiber density was found in the cerebellar cortex and 3H-5-hydroxytryptamine in vitro synaptosomal uptake was increased by 55%. Noradrenaline and 5-hydroxytryptamine concentrations in the cerebellum increased by 50 and 30%, respectively, whereas the total content of both neurotransmitters in cerebellum was approximately unchanged after methylazoxymethanol treatment. A significant reduction in total cerebellar in vitro binding of 3H-WB-4101 and 3H-dihydroalprenolol was also found, indicating compensatory receptor alterations following methylazoxymethanol treatment. The effect of combined treatment of methylazoxymethanol and the neurotoxin 6-hydroxydopamine (50 mg/kg s.c., day 1) showed a very pronounced reduction of noradrenaline concentration in cortex cerebri, while the noradrenaline concentration in cerebellum was increased by 185% and the tyrosine hydroxylase immunoreactive fiber density by 125%, indicating an additional relative hyperinnervation of cerebellar noradrenaline fiber due to a "pruning effect" of the 6-hydroxydopamine treatment. The results imply a relatively rigid development of terminal arborization of central nervous system monoamine neurons, relatively independent of neuronal and glial arrangement in the target area.
Luthman
J
J
Department of Histology and Neurobiology, Karolinska Institut, Stockholm, Sweden.
Eriksdotter-Nilsson
M
M
Jonsson
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001391:Azo Compounds / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism*; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006892:Hydroxydopamines / Q000494:pharmacology*; D007150:Immunohistochemistry; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology*; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000970:Antineoplastic Agents; D001391:Azo Compounds; D015306:Biogenic Monoamines; D005904:Glial Fibrillary Acidic Protein; D006892:Hydroxydopamines; D008746:Methylazoxymethanol Acetate; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; C030667:methylazoxymethanol