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Effect of postnatal methylmalonate administration on adult rat behavior
J C Dutra1, M Wajner, C M Wannmacher
1Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brasil.
Abstract:
1. Methylmalonate (MMA) levels (2.0-2.5 mM) comparable to those of human methylmalonic acidemia were achieved in blood of young rats from the 5th to the 25th day of life by injecting the drug subcutaneously twice a day with an interval of 8 h. MMA doses ranged from 0.76 to 1.69 mumol/g body weight as a function of animal age. MMA-treated rats had normal body and brain weights. 2. Behavioral studies using aversive and nonaversive tasks were performed at 60 days of life. Motor activity was similar in MMA-treated and saline-treated controls. No differences in performance between these groups were identified in the shuttle-avoidance responses and in the inhibitory avoidance tasks. However, MMA-injected rats escaped footshock faster than the controls (1.22 +/- 0.11 vs 1.76 +/- 0.14 (mean +/- SEM) for 24 rats in each group (P less than 0.01)) suggesting that they may be hyperreactive to this stimulus. 3. In the open field, a nonaversive behavior task, MMA-injected rats, in contrast to control rats, presented no habituation. 4. Our results suggest that MMA by itself may impair central nervous system function, causing minor disabilities which result in specific learning deficiencies.
Insights
Methylmalonate (MMA) administration in young rats induced central nervous system changes. These changes resulted in specific learning deficiencies, suggesting MMA impairs cognitive function.
Area of Science:
- Neuroscience
- Toxicology
- Developmental Biology
Background:
- Methylmalonic acidemia is a rare genetic disorder.
- Elevated methylmalonate (MMA) levels are characteristic of this condition.
- Understanding MMA's effects on the central nervous system (CNS) is crucial.
Purpose of the Study:
- To investigate the direct effects of methylmalonate (MMA) on the developing central nervous system (CNS) in a rat model.
- To assess behavioral and learning deficits induced by MMA exposure.
Main Methods:
- Young rats were administered methylmalonate (MMA) subcutaneously twice daily.
- MMA doses were adjusted based on animal age, achieving blood levels similar to human methylmalonic acidemia.
- Behavioral studies, including aversive and non-aversive tasks, were conducted at 60 days of age.
Main Results:
- MMA-treated rats exhibited normal body and brain weights.
- No significant differences in motor activity or shuttle-avoidance responses were observed compared to controls.
- MMA-injected rats showed faster footshock escape and a lack of habituation in the open field test, suggesting hyperreactivity and impaired learning.
Conclusions:
- Methylmalonate (MMA) exposure during development can impair central nervous system (CNS) function.
- These impairments manifest as specific learning deficiencies and altered behavioral responses.
- MMA may directly contribute to neurological deficits observed in methylmalonic acidemia.