Programming of brainstem serotonin transporter development by prenatal glucocorticoids.
Prenatal stress or exposure to excess glucocorticoids are known to alter central nervous system function and to result in lasting changes in reactions to stress. The potential involvement of specific elements of brainstem serotonergic neurons was examined in the current study. Pregnant rats were given 0.05, 0.2 or 0.8 mg/kg of dexamethasone on gestational days 17, 18 and 19, and the effects on development of the serotonin presynaptic transporter were assessed from birth to young adulthood by measurement of [3H]paroxetine binding to membrane preparations. Dexamethasone produced a dose-dependent retardation of body and brainstem growth but evoked a significant elevation of [3H]paroxetine binding that persisted into adulthood. Effects on [3H]paroxetine binding were robust even at the lowest dose, which did not suppress growth, indicating that the programming of this transporter is more sensitive to glucocorticoids than is general development. At the highest dose, promotional effects on serotonin transporter expression were offset by impaired growth, so that the peak effect was seen at the intermediate dose of dexamethasone. There were no comparable effects on serotonin transmitter levels, indicating selectivity toward promotion of transporter expression as distinct from simply increasing the number of serotonergic nerve terminals or all nerve terminal components. As the effect of prenatal dexamethasone treatment on the serotonin transporter is more persistent than those on other monoamine transporters, and is not shared by postnatal treatment or by treatment in adulthood, it likely represents specific programming by glucocorticoids during the prenatal period. Aberrant serotonergic transporter expression may contribute to alterations of synaptic function that ultimately produce the physiological abnormalities seen after prenatal stress or glucocorticoid treatment.
Slotkin
T A
TA
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710, USA.
Barnes
G A
GA
McCook
E C
EC
Seidler
F J
FJ
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D001933:Brain Stem / Q000737:chemistry* / Q000166:cytology / Q000196:embryology; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000378:metabolism; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D017374:Paroxetine / Q000378:metabolism / Q000494:pharmacology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium
D002352:Carrier Proteins; D003907:Dexamethasone; D005938:Glucocorticoids; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017374:Paroxetine; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014316:Tritium; C493232:Slc6a4 protein, rat