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

Abstract

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.

Long-term follow-up of prenatally treated children at risk for congenital adrenal hyperplasia: does dexamethasone cause behavioural problems?

“…In rats, a range of adverse effects has been observed upon prenatal GC treatment: low birth weight and hypertension (16), decreased size of the hippocampus and affected short-term memory (9) and alterations in structural brain development as well as in different neurotransmitter systems (17)(18)(19). Behavioural inhibition has also been observed in rats exposed to DEX during the entire gestational period or during late gestation (20).…”

CNS effects of developmental Pb exposure are enhanced by combined maternal and offspring stress

“…Ascending serotonergic systems appear to contribute to glucocorticoid-induced HPA programming prenatally (Slotkin et al 1996;Dean and Matthews 1999;Meaney et al 2000;Slotkin et al 2006). Changes in levels of 5-HT and metabolites have been reported in response to prenatal stress, as have behavioral changes in response to administration of serotonergic compounds (Ishiwata et al 2005).…”

Detrimental effects of glucocorticoids on neuronal migration during brain development

“…We used a synthetic compound, DEX, for the in vivo experiments, because it has a high affinity for the GR and is resistant to degradation by placental 11-b-hydroxysteroid dehydrogenase type 2 (11bHSD2). 28 As the GR mRNA is reported to be highly expressed throughout the brain from midgestation, 29 DEX (200 mg kg À1 ) 30 was injected into pregnant rats daily during the last week of gestation (from E14.5 to E20.5). In this period, cell proliferation of NPCs occurs in the VZ, and postmitotic immature neurons actively migrate to the CP.…”