¹Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA

Correspondence: Dr TA Slotkin, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813 DUMC, Room C162, LSRC Building, Research Drive, Durham, NC 27710, USA. Tel: 919 681 8015; Fax: 919 684 8197; E-mail: t.slotkin@duke.edu

Received 14 March 2005; Revised 19 April 2005; Accepted 25 April 2005; Published online 25 May 2005.

Abstract

Glucocorticoids administered to prevent respiratory distress in preterm infants are associated with neurodevelopmental disorders. To evaluate the long-term effects on forebrain development, we treated developing rats with dexamethasone (Dex) at 0.05, 0.2, or 0.8 mg/kg, doses below or spanning the range in clinical use, testing the effects of administration during three different stages: gestational days 17–19, postnatal days 1–3, or postnatal days 7–9. In adulthood, we assessed biomarkers of neural cell number and size, cholinergic presynaptic activity, neurotransmitter receptor expression, and synaptic signaling mediated through adenylyl cyclase (AC), in the cerebral cortex, hippocampus, and striatum. Even at doses that were devoid of lasting effects on somatic growth, Dex elicited deficits in the number and size of neural cells, with the largest effect in the cerebral cortex. Indices of cholinergic synaptic function (choline acetyltransferase, hemicholinium-3 binding) indicated substantial hyperactivity in males, especially in the hippocampus, effectively eliminating the normal sex differences for these parameters. However, the largest effects were seen for cerebrocortical cell signaling mediated by AC, where Dex treatment markedly elevated overall activity while obtunding the function of G-protein-coupled catecholaminergic or cholinergic receptors that stimulate or inhibit AC; uncoupling was noted despite receptor upregulation. Again, the effects on signaling were larger in males and offset the normal sex differences in AC. These results indicate that, during critical developmental periods, Dex administration evokes lasting alterations in neural cell numbers and synaptic function in forebrain regions, even at doses below those used in preterm infants.