Functional effects of methylazoxymethanol-induced cerebellar hypoplasia in rats.
The behavioral effects of a series of methylazoxymethanol acetate (MAM) injections in neonatal rats were investigated. Pups were injected twice daily on days 5-8 after birth with 4 mg/kg MAM or saline. Similar treatment paradigms cause cerebellar hypoplasia, which is a result of a depletion of granule cells. MAM treatment reduced adult cerebellar weight to 92% that of control and was without effect on weight of other brain regions examined. Postweaning body weight gain in males was reduced. Nest odor preference and emergence (light/dark box) assessments indicated no significant effects. Complex maze assessments and performance in an operant test battery demonstrated no cognitive deficits. Indeed, MAM treated females performed better in a complex maze under lighted conditions than same-sex controls. Open field and running wheel activity levels in females were unaffected. Though not statistically significant, males exhibited a mild hyperactivity syndrome characterized by an increase in running wheel and open field activity, as well as a depressed startle response. Both sexes were hypersensitive to the locomotor-increasing effects of methamphetamine. These results suggest that the functional effects resulting from cerebellar hypoplasia produced by MAM treatment on PNDs 5-8 are milder than those resulting from MAM treatment beginning on the day of birth. The results are compared with other forms of cerebellar lesions and provide support for the hypothesis that early insult (day of birth or shortly after) produces hypoactivity whereas a later insult (day 4 or later after birth) produces a syndrome of hyperactivity.
Division of Reproductive & Developmental Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA. sferguson@nctr.fda.gov
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Ferguson
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Paule
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Holson
D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D002273:Carcinogens / Q000633:toxicity*; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D003216:Conditioning, Operant / Q000187:drug effects; D003624:Darkness; D005108:Extinction, Psychological / Q000187:drug effects; D005260:Female; D008027:Light; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008694:Methamphetamine / Q000494:pharmacology; D008746:Methylazoxymethanol Acetate / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012727:Sex Characteristics
D002273:Carcinogens; D008694:Methamphetamine; D008746:Methylazoxymethanol Acetate