Steroid modulation of central nervous GABAA receptor binding in three female rat brain areas during postnatal...

The ontogenetic development of gamma-aminobutyric acid type A (GABAA) receptors and their sensitivity to neuroactive steroid agonists were determined between birth and day 25 postnatally, using membrane fractions of distinct rat brain areas. At birth, the medulla oblongata (MED) reached adult numbers of GABA-binding sites whose affinity did not change significantly postpartum. In contrast, in the phylogenetically younger frontal cortex (FC) and cerebellum (CER), the number of binding sites increased in a linear fashion, albeit with a greater delay in the CER. Moreover, the affinity varied significantly with age, but in the opposite way. Despite unchanged basal binding in the MED, both the FC and the MED displayed significant increases in the number of GABAA-binding sites elicited by either 3 alpha-hydroxy-5 alpha-pregnane-20-one (THP) or 3 alpha, 21-dihydroxy-5 alpha-pregnane-20-one (THDOC) in vitro (final concentration 1 microM) for all ages investigated, but the magnitude of enhancement was age-dependent. At 15 days postpartum, both THP and THDOC enhanced the density of binding sites in MED with maximal increases by 485 or 462% of the control determined in the absence of steroids. However, the simultaneously observed decrease of affinity did not reach statistical significance. Likewise, in the FC the steroidal influence on affinity did not begin to change until 15 days postpartum. However, there was a significant increase in affinity coincident with a reduced increase in receptor density. The present results demonstrate a brain-area-specific ontogeny of GABAA receptors and developmental changes in the sensitivity of GABAA-binding sites to steroids.