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

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 p eriod 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 sei zures. Seizures maybe modulated by an increased glutamatergic neurotransmis sion to excitatory or inhibitory neurons on the basis of a changed gene exp ression of NR subunits. This hypothesis promoted the present study. Film autoradiograms and emulsion-coated brain sections following labeling o f cholinergic and GABAergic neuron populations were evaluated. NR subunit 1 (NR1) expression, studied with a probe recognizing all NR1 tra nscripts, was unchanged after withdrawal from chronic ethanol treatment: co mpared to control animals. Using probes specific for different splice segme nts 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 inv estigated (only single label experiments were performed with NR1 splice var iants). Withdrawing rats revealed a higher expression of NR subunit 2A (NR2 A) mRNA in GABAergic neurons. No changes could be observed at the regional level. Conversely, NR2B mRNA was not substantially altered in cholinergic a nd GABAergic neurons, but showed a decrease over brain areas. For both, NR2 C 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.