Characterisation of GABA(A) receptors in fetal, neonatal and adult ovine brain: region and age related changes and the effects of allopregnanolone.
Progesterone metabolites acting via GABA(A) receptors suppress central nervous system (CNS) activity. The aim of the present study was to examine binding characteristics of GABA(A) receptors in fetal, newborn and adult sheep brains using [(35)S]TBPS, and to determine the effects of allopregnanolone on this binding. Receptor affinity (K(D)) and density (B(MAX)) in the brainstem were not different in fetal, newborn (1-2 days old) and adult brains. In the hypothalamus K(D) and B(MAX) increased significantly in the fetus between 85 and 128 days gestation, and were then similar to postnatal and adult values. In the frontal cortex K(D) and B(MAX) increased progressively between 85 days and term ( approximately 147 days gestation), and were then not different from postnatal and adult values. The K(i) values for the GABA(A) receptor antagonist picrotoxin was similar at all ages. Allopregnanolone inhibited [(35)S]TBPS binding in the presence of 5 microM GABA, but enhanced binding in the absence of GABA. These results show that (i), functional GABA(A) receptors are present in the fetal brain from at least 85 days gestation; (ii), 3alpha-pregnane steroids modify receptor affinity in the late gestation fetal brain; and (iii) there are region-specific changes in GABA(A) receptor binding parameters. Steroid modulation of the GABA(A) receptor in the fetal brain is likely to influence fetal CNS activity in late gestation.
Crossley
K J
KJ
Department of Physiology, Monash University, Victoria 3168, Clayton, Australia. k.crossley@med.monash.edu.au
Walker
D W
DW
Beart
P M
PM
Hirst
J J
JJ
D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000196:embryology / Q000378:metabolism*; D001933:Brain Stem / Q000196:embryology / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus; D005625:Frontal Lobe / Q000196:embryology / Q000378:metabolism; D018756:GABA Antagonists / Q000494:pharmacology; D007031:Hypothalamus / Q000196:embryology / Q000378:metabolism; D008297:Male; D010852:Picrotoxin / Q000494:pharmacology; D011247:Pregnancy; D011280:Pregnanolone / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism*; D012756:Sheep; D013462:Sulfur Radioisotopes; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018756:GABA Antagonists; D010852:Picrotoxin; D011280:Pregnanolone; D011963:Receptors, GABA-A; D013462:Sulfur Radioisotopes; D005680:gamma-Aminobutyric Acid; C037476:tert-butylbicyclophosphorothionate