Chronic ethanol exposure and withdrawal influence NMDA receptor subunit and splice variant mRNA expression in the rat cerebral cortex

Chronic ethanol exposure and subsequent withdrawal are known to change NMDA receptor activity. This study examined the effects of chronic ethanol admi nistration and withdrawal on the expression of several NMDA receptor subuni t and splice variant mRNAs in the rat cerebral cortex. Ethanol dependence w as induced by ethanol vapour exposure. To delineate between seizure-induced changes in expression during withdrawal and those due to withdrawal per se , another group of naive rats was treated with pentylenetetrazol (PTZ) inje ction (30 mg/kg, i.p.). RNA samples from the cortices of chronically treate d and withdrawing animals were compared to those from pairfed controls. Cha nges in NMDA receptor mRNA expression were determined using ribonuclease pr otection assays targetting the NR2A, -2B, -2C and NR1-pan subunits as well as the three alternatively spliced NR1 inserts (NR1-pan describes all the k nown NR1 splice variants generated from the 5' insert and the two 3' insert s). The ratio of NR1 mRNA incorporating the 5' insert vs, that lacking it w as decreased during ethanol exposure and up to 48 h after withdrawal. NR2B mRNA expression was elevated during exposure, but returned to control level s 18 h after withdrawal. Levels of NR2A, NR2C, NR1-pan and both 3' NR1 inse rt mRNAs from the ethanol-treated groups did not alter compared with the pa ir-fed control group. No changes in the level of any NMDA receptor subunit mRNA was detected in the PTZ-treated animals. These data support the hypoth esis that changes in NMDA receptor subunit composition may underlie a neuro nal adaptation to the chronic ethanol-inhibition and may therefore be impor tant in the precipitation of withdrawal hyperactivity. (C) 1999 Elsevier Sc ience B.V. All rights reserved.