Changes in NMDA receptor subunit gene expression in the rat brain following withdrawal from forced long-term ethanol intake.

Abstract

Changes in mRNA levels of N-methyl-D-aspartate receptor (NR) subunits were studied in a rat model of withdrawal from forced ethanol ingestion over a period of 8 days. In part, this model may reflect the epsilon-type of human alcoholism according to Jellinek (College University Press, New Haven; 1972). The epsilon-type is characterized by dipsomania over a period of several days, recurring every few months and often followed by ethanol-induced seizures. Seizures may be modulated by an increased glutamatergic neurotransmission to excitatory or inhibitory neurons on the basis of a changed gene expression of NR subunits. This hypothesis promoted the present study. Film autoradiograms and emulsion-coated brain sections following labeling of cholinergic and GABAergic neuron populations were evaluated. NR subunit 1 (NR1) expression, studied with a probe recognizing all NR1 transcripts, was unchanged after withdrawal from chronic ethanol treatment compared to control animals. Using probes specific for different splice segments of NR1, however, we found that, in ethanol-treated rats, the expression of NR1-2 was decreased in all, and that of NR1-4 in all but one, areas investigated (only single label experiments were performed with NR1 splice variants). Withdrawing rats revealed a higher expression of NR subunit 2A (NR2A) mRNA in GABAergic neurons. No changes could be observed at the regional level. Conversely, NR2B mRNA was not substantially altered in cholinergic and GABAergic neurons, but showed a decrease over brain areas. For both, NR2C and NR2D, no ethanol-related changes of mRNA expression were observed. A link between such differential alterations in NR mRNA subunit expression and ethanol-induced seizures in withdrawing alcoholics of the epsilon-type seems possible.