Neurosteroid modulation of the GABAA receptor in the developing guinea pig cerebral cortex

Developmental changes in 5 alpha-pregnan-3 alpha-ol-20-one (allopregnanolone; 5 alpha-3 alpha-P) potentiation of muscimol and benzodiazepine binding to the GABA(A) receptor were studied in the guinea pig cerebral cortex at three prenatal ages (gestational day (GD) 40, GD 50, GD 62), and three postnatal ages (postnatal day (PD) 11, PD 21, PD 61) (term, about GD 68). The number and affinity of [H-3]flunitrazepam binding sites, and 5 alpha-3 alpha-P potentiation of [H-3]muscimol and [H-3]flunitrazepam binding to the GABA(A) receptor were determined at each age. There was no age effect on the affinity (K-d) for [H-3]flunitrazepam. However, the number (B-max) of [H-3]flunitrazepam binding sites doubled between GD 40 and GD 62, and then declined slightly to reach adult levels by PD 11. 5 alpha-3 alpha-P produced a concentration-dependent potentiation of [H-3]muscimol and [H-3]flunitrazepam binding at each developmental age examined. The potency thigh-affinity) for 5 alpha-3 alpha-P potentiation of both [H-3]muscimol and [H-3]flunitrazepam binding was lowest at GD 40, and increased to adult levels by GD 62. In contrast, the efficacy for 5 alpha-3 alpha-P potentiation of both [H-3]muscimol and [H-3]flunitrazepam binding was greatest at GD 40, and decreased to adult levels between GD 50 and GD 62. The percentage of high-affinity zolpidem binding sites increased in an age-dependent manner from 34.2 +/- 2.2% at GD 40, to reach adult levels by GD 62 (59.4 +/- 2.5%). These data suggest that 5 alpha-3 alpha-P can modulate GABA(A) receptors in the immature cerebral cortex, and that changes in 5 alpha-3 alpha-P action are temporally related to changes in GABA(A) receptor benzodiazepine pharmacology late in gestation in the guinea pig. (C) 1999 Elsevier Science B.V. All rights reserved.