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Development and behavioral outcomes of perinatal inhibition of ornithine decarboxylase
Abstract:
Rats were treated with alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), at a dose of 200 mg/kg/day SC, either prenatally (to the mothers, on days 16 to 20 of gestation) or neonatally (to the pups, on days 1 to 10 after birth). At this dose level neither maternal reproductive performance (prenatal treatment) nor gain in body weight on the part of offspring were affected. Earlier developmental alterations were rapidly overcome. Prenatally-treated rats proved less active than controls in the open field, performed better in passive avoidance retention (both preweaning and postweaning), and had a shorter post-ejaculatory interval in the male copulatory test. Postnatally-treated rats performed better than controls in two-way active avoidance conditioning, and in passive avoidance retention (as adults). Reproductive performance of the treated female offspring was similar to that of controls. ODC activity in brains of DFMO-exposed offspring was substantially inhibited throughout treatment (-72 to -41%, compared with respective controls), but showed a strong rebound after termination of treatment (up to +400%, compared with respective controls). These results show that partial inhibition of ODC activity during a limited period of the perinatal life has no adverse effect on the overall behavioral development of rats: indeed, some performances are actually improved. This being the most likely due to a rebound ODC hyperactivity after termination of treatment, when brain maturation is still in progress.
Insights
Alpha-difluoromethylornithine (DFMO) treatment during perinatal development in rats did not adversely affect overall behavioral development. Some behaviors, like passive avoidance, were actually improved, possibly due to rebound ODC hyperactivity.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Ornithine decarboxylase (ODC) plays a crucial role in cell growth and differentiation.
- Inhibiting ODC during critical developmental periods may impact neurodevelopment and behavior.
- Alpha-difluoromethylornithine (DFMO) is a potent irreversible inhibitor of ODC.
Purpose of the Study:
- To investigate the long-term effects of perinatal ODC inhibition by DFMO on rat behavior.
- To assess potential adverse effects on development, reproduction, and specific behavioral tasks.
- To examine the impact of DFMO on ODC activity in the developing brain.
Main Methods:
- Rats were administered DFMO (200 mg/kg/day SC) either prenatally or neonatally.
- Maternal and offspring reproductive performance, and offspring body weight gain were monitored.
- Behavioral assessments included open field activity, passive avoidance, copulatory tests, and active avoidance conditioning.
- Brain ODC activity was measured during and after DFMO treatment.
Main Results:
- DFMO treatment did not affect maternal reproduction or offspring body weight gain.
- Prenatally treated rats showed reduced open field activity but improved passive avoidance.
- Postnatally treated rats exhibited enhanced active and passive avoidance learning.
- ODC activity was inhibited during treatment but showed significant rebound hyperactivity post-treatment.
Conclusions:
- Perinatal partial inhibition of ODC by DFMO has no adverse effects on rat behavioral development.
- Specific behavioral performances, particularly in learning and memory, were improved.
- Rebound ODC hyperactivity following treatment cessation may contribute to enhanced behavioral outcomes during brain maturation.