Dose-dependent glucocorticoid effects on noradrenergic synaptogenesis in rat brain: ontogeny of [3H]desmethylimipramine binding sites after fetal exposure to dexamethasone.
Glucocorticoid administration slows the development of many types of cells, but may selectively accelerate differentiation of catecholaminergic cells. In the current study, pregnant rats were given dexamethasone on gestational days 17, 18 and 19 and noradrenergic synaptogenesis assessed in the offspring by measurements of binding capabilities for [3H]desmethylimipramine (DMI), a radioligand probe for noradrenergic presynaptic terminals. After treatment with 0.05 mg/kg of dexamethasone, a dose that did not suppress body or brain region growth, [3H]DMI was initially enhanced in midbrain + brainstem and in cerebellum; the former region also displayed a secondary phase of augmented [3H]DMI binding during the ontogenetic peak occurring in the second to third postnatal week. At a higher dose (0.2 mg/kg) that elicited moderate growth impairment, fetal dexamethasone exposure produced biphasic effects on [3H]DMI binding: initial enhancement was still apparent in cerebral cortex and cerebellum, but there were subsequent deficits in binding and the peak in midbrain + brainstem was shifted to later stages. At the highest dose (0.8 mg/kg), profound growth impairment was evident and only the cerebellum showed unequivocal evidence of enhanced [3H]DMI binding. All changes were associated with alterations in the maximum [3H]DMI binding capacity (Bmax) not in the binding affinity (Kd). These results suggest that low doses of dexamethasone that do not suppress general growth, enhance noradrenergic synaptogenesis in a regionally-selective and age-selective manner; at higher, growth-suppressing doses, this effect is intermixed with general delays in maturation, likely contributing to the variable effects of glucocorticoids on neurobehavioral development.
Slotkin
T A
TA
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710.
Lappi
S E
SE
Tayyeb
M I
MI
Seidler
F J
FJ
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D003891:Desipramine / Q000032:analysis / Q000378:metabolism*; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005333:Fetus / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D008431:Maternal-Fetal Exchange; D009638:Norepinephrine / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D013569:Synapses / Q000187:drug effects*
D005938:Glucocorticoids; D003907:Dexamethasone; D003891:Desipramine; D009638:Norepinephrine