Impaired development of central and peripheral catecholamine neurotransmitter systems in preweanling rats treated with alpha-difluoromethylornithine, a specific irreversible inhibitor of ornithine decarboxylase.

Daily administration of alpha-difluoromethylornithine (DFMO) to neonatal rats results in persistent inhibition of ornithine decarboxylase, depletion of polyamines and rapid onset of brain growth deficits. Animals treated with DFMO displayed marked retardation of synaptic development of catecholaminergic systems in the brain, evidenced by slowed development of synaptosomal uptake of [3H]norepinephrine and of tyrosine hydroxylase activity. Fundamental alterations in brain membrane metabolism also could be detected through measurements of phospholipid incorporation of 33Pi; DFMO suppressed the developmental increments in phospholipid synthesis normally accompanying synaptic outgrowth. Although the content of norepinephrine and dopamine in the brain was unchanged by DFMO, the drug did cause initial reductions, and subsequent elevations, in catecholamine turnover. Effects of DFMO on development of peripheral sympathetic neurons were even more profound, with substantial deficits in norepinephrine content throughout preweanling development, again accompanied by biphasic alterations of turnover. The adrenal medulla, a sympathetic tissue which does not undergo catecholaminergic axonal outgrowth and synaptogenesis, was spared the deleterious effects of DFMO on development. These results support the view that ornithine decarboxylase and the polyamines play an obligatory role in synaptic maturation, with the greatest sensitivity to DFMO-induced alterations occurring during periods of rapid development.

Duke Scholars

Author Theodore Alan Slotkin Pharmacology & Cancer Biology

Author Frederic J. Seidler Pharmacology & Cancer Biology