Critical prenatal and postnatal periods for persistent effects of dexamethasone on serotonergic and dopaminergic systems.
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 5HT1A and 5HT2 receptors and the presynaptic 5HT transporter, greatest for 5HT1A 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.
Slotkin
Theodore A
TA
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Kreider
Marisa L
ML
Tate
Charlotte A
CA
Seidler
Frederic J
FJ
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development; D002658:Developmental Disabilities / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D003907:Dexamethasone / Q000009:adverse effects*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009434:Neural Pathways / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D005938:Glucocorticoids; D011985:Receptors, Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D003907:Dexamethasone; D004298:Dopamine; D006719:Homovanillic Acid