Early postnatal ethanol intubation blunts GABA(A) receptor up-regulation and modifies 3alpha-hydroxy-5alpha-pregnan-20-one sensitivity in rat MS/DB neurons.
Previously we found postnatal binge-like ethanol exposure using an artificial-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 cerebellar Purkinje neurons. In the present study, the impact of ethanol on developing GABA(A)Rs in MS/DB neurons was further tested under conditions not requiring anesthesia or maternal deprivation. Nursing rat pups received ethanol (4.5-5.25 g/kg/day) on postnatal days (PD) 4-9, which was administrated manually by oral intragastric intubation. This treatment caused dose-dependent blunting of peak GABA(A) receptor whole cell currents in acutely dissociated MS/DB cells on PD 12-15. The threshold with oral intubation was slightly higher than previously observed for artificial-rearing (4.9 vs. 4.5 g/kg/day). The previously observed reduced sensitivity of GABA(A)Rs to Zn(2+)-inhibition after ethanol was not found with the intubation model. In studies only carried out using the intubation method, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha-OH-DHP) caused an allosteric concentration-dependent potentiation of currents activated by non-saturated concentrations of GABA. A bicuculline sensitive direct activation of GABA(A)Rs also occurred with higher concentrations of 3alpha-OH-DHP alone. Ethanol intubation up-regulated allosteric neurosteroid potentiation with low concentrations of GABA, but did not change direct agonist actions of 3alpha-OH-DHP. Finally, 3alpha-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 binge-type ethanol exposure models and may increase positive modulation of GABA(A) receptors by endogenous neurosteroids.
Hsiao
S H
SH
Department of Medical Pharmacology and Toxicology, College of Medicine, Texas A&M University System Health Science Center, College Station, TX 77843-1114, USA.
Acevedo
J L
JL
DuBois
D W
DW
Smith
K R
KR
West
J R
JR
Frye
G D
GD
D000367:Age Factors; D000494:Allosteric Regulation; D000818:Animals; D000833:Animals, Suckling; D000927:Anticonvulsants / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D007441:Intubation, Gastrointestinal; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016548:Prosencephalon / Q000166:cytology; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D015032:Zinc / Q000494:pharmacology
D000927:Anticonvulsants; D002492:Central Nervous System Depressants; D011963:Receptors, GABA-A; D000431:Ethanol; C105051:ganaxolone; D011280:Pregnanolone; D015032:Zinc