Development of GABAA receptors on medial septum/diagonal band (MS/DB) neurons after postnatal ethanol exposure.
The impact of 'binge-like' ethanol exposure on postnatal days (PD) 4-9 was examined on development of gamma-aminobutyric acid type A receptors (GABAAR) during the first month of life in the rat. Whole-cell patch-clamp recordings in acutely isolated medial septum/diagonal band (MS/DB) neurons were used to define effects of rapidly applied ethanol and other allosteric modulators on bicuculline-sensitive GABA currents. Three age groups were examined including 'pups' (PD 4-10), 'juveniles' (PD 11-16) and 'young adults' (PD 25-35). In untreated neurons, maximum responses to GABA and the apparent GABA EC50 increased approximately 2-fold during the first month of life. Potentiation of GABA responses by pentobarbital, midazolam, and loreclezole all increased with age, while Zn2+ inhibition declined. Initial inhibition by ethanol switched to potentiation of GABA responses during this time. In vivo, binge-like ethanol treatment (4.5 g kg-1 day-1 divided into two doses, 2 h apart on PD 4-9) reduced both the GABA maximal response and GABA EC50 measured on PD 11-16. These measures returned to control levels by PD 25-35. After binge-like postnatal ethanol exposure, age-dependent loss of Zn2+ inhibition of GABA responses was increased, while potentiating actions of in vitro ethanol were blocked. GABAAR modulation by other drugs was unaffected. These data suggest that early postnatal ethanol exposure disrupts the expected developmental pattern of GABAAR function in MS/DB neurons, an action that could contribute to neurobehavioral deficits associated with the fetal alcohol syndrome. Whether these changes are due to cellular damage, delayed gene expression or post-translational modification needs to be determined.
Hsiao
S H
SH
Department of Medical Pharmacology and Toxicology, College of Medicine, Texas A&M Health Science Center, College Station, TX 77843-1114, USA.
Mahoney
J C
JC
West
J R
JR
Frye
G D
GD
D000465:Algorithms; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000254:growth & development*; D001923:Brain Chemistry / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D005260:Female; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*
D002492:Central Nervous System Depressants; D011963:Receptors, GABA-A; D000431:Ethanol