Early postnatal ethanol intubation blunts GABA(A) receptor up-regulation and modifies 3 alpha-hydroxy-5 alpha-pregnan-20-one sensitivity in rat MS/DBneurons

Previously we found postnatal binge-like ethanol exposure using an artifici al-rearing method in the rat delayed developmental up-regulation of GABA(A) receptors (GABA(A)Rs) in both medial septum/diagonal band (MS/DB) and cere bellar Purkinje neurons. In the present study, the impact of ethanol on dev eloping GABA(A)Rs in MS/DB neurons was further tested under conditions not requiring anesthesia or maternal deprivation. Nursing rat pups received eth anol (4.5-5.25 g/kg/day) on postnatal days (PD) 4-9, which was administrate d manually by oral intragastric intubation. This treatment caused dose-depe ndent blunting of peak GAB(A), receptor whole cell currents in acutely diss ociated MS/DB cells on PD 12-15. The threshold with oral intubation was sli ghtly higher than previously observed for artificial-rearing (4.9 vs. 4.5 g /kg/day). The previously observed reduced sensitivity of GAB(A)Rs. to Zn2+- inhibition after ethanol was not found with the intubation model. In studie s only carried out using the intubation method, 3 alpha -hydroxy-5 alpha -p regnan-20-one (3 alpha -OH-DHP) caused an allosteric concentration-dependen t potentiation of currents activated by non-saturated concentrations of GAB A. A bicuculline sensitive direct activation of GABARs also occurred with h igher concentrations of 3 alpha -OH-DHP alone. Ethanol intubation up-regula ted allosteric neurosteroid potentiation with low concentrations of GABA, b ut did not change direct agonist actions of 3 alpha -OH-DHR Finally, 3 alph a -OH-DHP did not prime ethanol insensitive GABA(A)Rs to become sensitivity to acute ethanol potentiation. These results indicate ethanol consistently blunts postnatal GABA(A) receptor up-regulation across early postnatal bin ge-type ethanol exposure models and may increase positive modulation of GAB A(A) receptors by endogenous neurosteroids. (C) 2001 Elsevier Science B.V. All rights reserved.