EFFECTS OF GESTATIONAL OR NEONATAL TREATMENT WITH ALPHA-DIFLUOROMETHYLORNITHINE ON ORNITHINE DECARBOXYLASE AND POLYAMINES IN DEVELOPING RAT-BRAIN AND ON ADULT-RAT NEUROCHEMISTRY

Pregnant rats were treated for five consecutive days during gestation with s.c. injections of the ornithine decarboxylase (ODC) inhibitor al pha-difluoromethylornithine (DFMO). Treatment beginning at gestational days 13 or 14 was effective in inhibiting ODC and altering polyamine levels, and resulted in relatively small decreases in body and forebra in weight, but not in significant differences in adult neurochemistry. Neonatal rats were treated with DFMO from postnatal day 0 (PD 0) to P D 24. In addition to some somatic effects (decreased body weight, dela yed eyelid opening and delayed fur growth) the postnatal treatment res ulted in a permanent decrease in brain weight, which was mainly due to a dramatic decrease in cerebellar size. During treatment, and 3 days after the end of it, the levels of putrescine and spermidine, but not those of spermine, were consistently lower in the cerebellum and foreb rain of DFMO-treated rats than in controls. On the other hand, ODC app eared strongly inhibited only during the first phase of the treatment and showed recovery, and also rebound of the activity, during the seco nd part of the treatment. A screening of neurochemical markers related to cholinergic, GABAergic and glutamatergic neurons, as well to astro cytes and oligodendrocytes was performed in several brain regions (cer ebellum, olfactory bulbs, cortex, striatum, hippocampus) of some of th ese rats once they became adults. Significant alterations for all the parameters tested, with the exception of the marker for the gluta- mat ergic transmission, were measured in the undersized cerebellum of the neonatally DFMO-treated rats. A shorter neonatal treatment with DFMO ( from PD 1 to 6) resulted, in the adult, in decreased cerebellar size a nd in neurochemical alterations, both very similar to those oc curring after the prolonged treatment. In the other brain regions a few minor differences were noticed. The present results show that: (1) the brai n polyamine system is differently regulated in foetuses with respect t o newborns; (2) the effects of chronic ODC blockade are different on p renatally or postnatally proliferating neurons, due either to a lower sensitivity of gestationally proliferating neurons or to a subsequent recovery; and (3) chronic postnatal ODC inhibition has a strong effect on proliferating neurons, but little effect on further maturation of postmitotic neurons.