Early postnatal effects of prenatal exposure to glucocorticoids on testosterone metabolism and biogenic monoamines in discrete neuroendocrine regions of the rat brain

Levin

Seidler

et al. 2005

Glucocorticoids are the consensus treatment for preventing respiratory distress syndrome in preterm infants but there is emerging evidence of subsequent neurobehavioral abnormalities, independent of somatic growth effects. Pregnant rats were given 0.2 mg/kg of dexamethasone, a dose commensurate with clinical use, on gestational days 17-19 and behavioral evaluations were made on the offspring in adolescence and adulthood. The dexamethasone groups had the same body weights as the controls but nevertheless displayed long-term, sex-selective alterations in locomotor and cognitive behaviors. In the figure-8 activity apparatus, dexamethasone treatment ablated the normal sex differences in locomotor activity by reducing values in females to the lower level typical of males; habituation of activity similarly was impaired in females, reducing the profile to match that of control males, while male rats in the dexamethasone group showed a partially feminized pattern of habituation. In the 8-arm radial maze, control rats displayed typical sex differences, with male rats performing more accurately than females. Dexamethasone treatment eliminated this normal dichotomy, delaying learning in males while improving performance in females to the level normally seen in control males. Finally, we assessed hippocampal [3 H]hemicholinium-3 binding as a biomarker for cholinergic synaptic activity, and again found loss of sex differences in the dexamethasone group: values in males were increased to the higher levels typical of females. These results indicate that gestational treatment with dexamethasone obtunds the normal sex differences in neurochemistry and behavior that are typically seen in adolescence in adulthood, thus producing sex-selective alterations in activity, learning, and memory.

Section: Discussionmentioning

confidence: 95%

Gestational Dexamethasone Treatment Elicits Sex-Dependent Alterations in Locomotor Activity, Reward-Based Memory and Hippocampal Cholinergic Function in Adolescent and Adult Rats

Levin

Seidler

et al. 2005

“…Of further interest, the effects of Dex on adrenergic receptor expression and on bAR-mediated AC stimulation were among the only ones in which we found a sharp distinction between males and females. Dex influences testosterone synthesis and metabolism (Reznikov et al, 2004) and in turn, testosterone regulates the expression of a 2 ARs (Dygalo et al, 2002). Although parallel studies have not been conducted for sex-dependent effects on bAR expression, there are steroid-binding sites in the bAR promoter (Cornett et al, 1998), so that such differences may also exist for this receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Both of these transmitters play a critical role as trophic factors in development of the forebrain (Dreyfus, 1998;Hohmann, 2003;Hohmann and Berger-Sweeney, 1998;Lauder and Schambra, 1999;Whitaker-Azmitia, 1991) and are likely targets for developmental effects of glucocorticoids (Hu et al, 1996;Muneoka et al, 1997;Reznikov et al, 2004;Shi et al, 1998;Slotkin et al, 1982;Zahalka et al, 1993b). We evaluated choline acetyltransferase (ChAT) activity and the binding of [ 3 H]hemicholinium-3 (HC3) to the high-affinity presynaptic choline transporter.…”

Section: Introductionmentioning

confidence: 99%

Disruption of Rat Forebrain Development by Glucocorticoids: Critical Perinatal Periods for Effects on Neural Cell Acquisition and on Cell Signaling Cascades Mediating Noradrenergic and Cholinergic Neurotransmitter/Neurotrophic Responses

Aldridge

Cousins

et al. 2005

Glucocorticoids are the consensus treatment for the prevention of respiratory distress in preterm infants, but there is evidence for increased incidence of neurodevelopmental disorders as a result of their administration. We administered dexamethasone (Dex) to developing rats at doses below or within the range of those used clinically, evaluating the effects on forebrain development with exposure in three different stages: gestational days 17-19, postnatal days 1-3, or postnatal days 7-9. At 24 h after the last dose, we evaluated biomarkers of neural cell acquisition and growth, synaptic development, neurotransmitter receptor expression, and synaptic signaling mediated by adenylyl cyclase (AC). Dex impaired the acquisition of neural cells, with a peak effect when given in the immediate postnatal period. In association with this defect, Dex also elicited biphasic effects on cholinergic presynaptic development, promoting synaptic maturation at a dose (0.05 mg/kg) well below those used therapeutically, whereas the effect was diminished or lost when doses were increased to 0.2 or 0.8 mg/kg. Dex given postnatally also disrupted the expression of adrenergic receptors known to participate in neurotrophic modeling of the developing brain and evoked massive induction of AC activity. As a consequence, disparate receptor inputs all produced cyclic AMP overproduction, a likely contributor to disrupted patterns of cell replication, differentiation, and apoptosis. Superimposed on the heterologous AC induction, Dex impaired specific receptor-mediated cholinergic and adrenergic signals. These results indicate that, during a critical developmental period, Dex administration leads to widespread interference with forebrain development, likely contributing to eventual, adverse neurobehavioral outcomes.

“…We then focused on the effects directed toward two specific neurotransmitter systems, acetylcholine and norepinephrine, both of which are likely targets for developmental effects of glucocorticoids (Hu et al, 1996;Kreider et al, 2005a, b;Muneoka et al, 1997;Reznikov et al, 2004;Shi et al, 1998;Slotkin et al, 1982;Zahalka et al, 1993b). Acetylcholine systems were evaluated with assays of choline acetyltransferase (ChAT) activity and the binding of [ 3 H]hemicholinium-3 (HC3) to the high-affinity presynaptic choline transporter.…”

Section: Introductionmentioning

confidence: 99%

Lasting Effects of Developmental Dexamethasone Treatment on Neural Cell Number and Size, Synaptic Activity, and Cell Signaling: Critical Periods of Vulnerability, Dose–Effect Relationships, Regional Targets, and Sex Selectivity

Tate

Cousins

et al. 2005

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.