Critical development periods for inhibition of ornithine decarboxylase by alpha-difluoromethylornithine: effects on ontogeny of sensorimotor behavior.

The roles of ornithine decarboxylase and the polyamines in behavioral development were examined through the use of alpha-difluoromethylornithine, a specific irreversible inhibitor of ornithine decarboxylase. alpha-Difluoromethylornithine was administered either prenatally during gestation (days 15-17) or postnatally (days 1-20) to examine critical periods of sensitivity. Prenatal alpha-difluoromethylornithine administration resulted in a deficit in early sensorimotor ontogeny: latencies in surface righting reflex (postnatal days 1-5) and negative geotaxis (postnatal days 5-8) were prolonged, and time spent pivoting (postnatal days 7, 9, and 11) was reduced. In contrast, postnatal alpha-difluoromethylornithine primarily influenced later maturing, complex integrative behaviors such as swimming and open field activity. Thus, the behavioral effects of alpha-difluoromethylornithine exposure are highly dependent upon the age at which the drug is administered, a finding in keeping with the participation of the ornithine decarboxylase/polyamine system in cell replication and differentiation during discrete periods of neural development. The behavioral consequences of ornithine decarboxylase inhibition during these critical periods are thus related primarily both to the timetable for cellular maturation in each brain region.

Duke Scholars

Author Theodore Alan Slotkin Pharmacology & Cancer Biology