3Alpha-hydroxy-5alpha-pregnan-20-one levels and GABA(A) receptor-mediated 36Cl(-) flux across development in rat cerebral cortex.
Despite considerable evidence showing dramatic changes in the plasticity of GABA(A) receptors during neuronal development and studies showing a direct link between neurosteroid concentrations and alterations in GABA(A) receptor expression, little is known about the role of neurosteroids in GABA(A) receptor plasticity early in development. The relationship between changes in brain concentrations of 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone, 3alpha,5alpha-THP) and GABA(A) receptor function in the brain during early development was investigated in rats. The concentration in fetal forebrain of the pregnane metabolite 3alpha,5alpha-THP declined precipitously prior to parturition, before returning to normal (adult male) values on the day of birth (P0). Postnatal cortical 3alpha,5alpha-THP levels remain quite low (<2 ng/g) until postnatal day 10 (PD10) and PD14 when we found elevated cortical 3alpha,5alpha-THP levels (3.3+/-0.8 and 3.8+/-0.9 ng/g, respectively). These levels reverted to basal values by PD15 (0.56+/-0.4 ng/g). We examined GABA(A) receptor-mediated 36Cl(-) flux in cortex of PD7, PD12 and PD16 rat brain. We found a 32% reduction in the stimulation (apparent E(max)) of 36Cl(-) uptake by muscimol in PD12 tissue relative to adult. The potentiating effects of 3alpha,21-dihydroxy-5alpha-pregnane-20-one (tetrahydrodeoxycorticosterone, THDOC) and flunitrazepam were decreased in PD12 tissue. These data provide a better understanding of potential contributions endogenous GABAergic neurosteroids may make to normal neuronal development.
Grobin
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Department of Psychiatry, CB #7178, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7178, USA. grobinac@med.unc.edu
Morrow
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D000494:Allosteric Regulation; D000818:Animals; D000831:Animals, Newborn; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism*; D002713:Chlorine / Q000493:pharmacokinetics; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005445:Flunitrazepam / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D007743:Labor, Obstetric; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D011247:Pregnancy; D011280:Pregnanolone / Q000378:metabolism*; D011868:Radioisotopes / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D012727:Sex Characteristics
D014151:Anti-Anxiety Agents; D018755:GABA Agonists; D018757:GABA Modulators; D011868:Radioisotopes; D011963:Receptors, GABA-A; D009118:Muscimol; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D002713:Chlorine; D005445:Flunitrazepam; D011280:Pregnanolone