Prenatal Glucocorticoid Modifies Hypothalamo-Pituitary-Adrenal Regulation in Prepubertal Guinea Pigs

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: 99%

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

“…We recently found that Dex treatment, even at doses that do not compromise long-term somatic growth, nevertheless disrupts cell acquisition, indices of neuritic outgrowth, synaptic activity, and cell signaling involved in trophic regulation of forebrain development (Kreider et al, 2005a). These effects were associated with long-term changes in motor and social activities, and cognitive performance (Kamphuis et al, 2003(Kamphuis et al, , 2004Kreider et al, 2005b), resembling those seen in models of prenatal stress (Bowman et al, 2004;Dean et al, 2001;Felszeghy et al, 2000;Muneoka et al, 1997). The vulnerability of the forebrain to developmental disruption by Dex represents the targeting of peak periods of neuronal cell replication and differentiation in the perinatal period (Bell et al, 1986;Rodier, 1988), combined with high expression of glucocorticoid receptors (Speirs et al, 2004) and an inability of the developing organism to limit glucocorticoid effects by downregulating the receptors (Ghosh et al, 2000).…”

Section: Introductionmentioning

confidence: 90%

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.

“…To bridge the gap, we recently performed studies in developing rats, showing that Dex treatment, even at doses that lie below those used in the therapy of preterm delivery and that do not compromise long-term somatic growth, nevertheless disrupts neural cell acquisition, indices of neuritic outgrowth, synaptic activity and cell signaling involved in trophic regulation of forebrain development (Kreider et al, 2005a). These effects were associated with long-term changes in cognition and motor activity (Kreider et al, 2005b), resembling those seen in models of prenatal stress (Bowman et al, 2004;Dean et al, 2001;Felszeghy et al, 2000;Muneoka et al, 1997). Interestingly, the persistent effects on cholinergic synaptic function showed regional selectivity and critical periods of vulnerability that differed from the general effects on neural cell acquisition and development (Kreider et al, 2006).…”

Section: Introductionmentioning

confidence: 97%

Critical Prenatal and Postnatal Periods for Persistent Effects of Dexamethasone on Serotonergic and Dopaminergic Systems

Slotkin

Tate

et al. 2005

Glucocorticoid administration to preterm infants is associated with neurodevelopmental disorders. 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 the impact on synaptic biomarkers for serotonin (5-hydroxytryptamine (5HT)) systems. Across all three regimens, Dex administration evoked upregulation of cerebrocortical 5HT 1A and 5HT 2 receptors and the presynaptic 5HT transporter, greatest for 5HT 1A receptors. The effects were fully evident even at the lowest dose. In contrast, 5HT levels in the cerebral cortex and hippocampus showed disparate patterns of temporal sensitivity, with no change after gestational treatment, an increase with the early postnatal regimen, and a decrease with the later postnatal exposure. None of the changes in 5HT concentrations were offset by adaptive changes in the fractional 5HT turnover rate. Furthermore, the critical period of sensitivity seen for 5HT levels differed from that of dopamine even within the same brain region. These findings suggest that developmental exposure to Dex during the critical neurodevelopmental period corresponding to its use in preterm infants, elicits selective changes in 5HT and dopaminergic synaptic function over and above its effects on general aspects of neural cell development, below the threshold for somatic growth impairment, and even at doses below those used clinically. Accordingly, adverse neurobehavioral consequences may be inescapable in glucocorticoid therapy of preterm infants. Neuropsychopharmacology (2006) 31, 904-911.