Regional and subunit specific changes in NMDA receptor mRNA and immunoreactivity in mouse brain following chronic ethanol ingestion.

Chronic ethanol treatment of mice has been shown to result in increased binding of dizocilpine and glutamate to hippocampal NMDA receptors. These changes were suggested to reflect an increase in NMDA receptor number that may underlie certain signs of the ethanol withdrawal syndrome. However, there was no change in binding of a competitive NMDA receptor antagonist, or of ligand binding to the glycine co-agonist site on the receptor after chronic ethanol treatment. Differential changes in the binding of particular ligands at the NMDA receptor suggested the possibility that chronic ethanol ingestion might selectively affect the expression of particular NMDA receptor subunits. Our current work demonstrates that chronic ethanol ingestion by mice, which results in the generation of physical dependence, also produces increases in the NMDA receptor NR1 subunit protein in the hippocampus and cerebellum (approximately 50% and 95%, respectively), and produces increases in the NR2A subunit protein in the hippocampus and cortex (approximately 25% and 40%, respectively). However, the mRNA levels for these subunits were not increased in the respective brain areas by the same ethanol treatment. The changes in NMDA receptor subunit expression in discrete areas of the brain may contribute to the previously observed changes in ligand binding and, possibly, signs of ethanol withdrawal.

Antisense oligonucleotide to c-fos blocks the ability of arginine vasopressin to maintain ethanol tolerance.

Administration of the neuropeptide, arginine vasopressin, can reduce the rate of dissipation of functional ethanol tolerance in mice that have acquired that tolerance. We previously showed that intracerebroventricular vasopressin administration can also produce an increase in septal c-fos mRNA levels. To evaluate the role of the increased expression of c-fos in the ability of vasopressin to maintain tolerance, ethanol-tolerant mice were given intracerebroventricular injections of vasopressin in the presence or absence of an antisense oligonucleotide to c-fos. The antisense oligonucleotide completely blocked the ability of vasopressin to maintain ethanol tolerance, while a missense oligonucleotide was without effect. The antisense oligonucleotide also attenuated the increase in septal c-fos mRNA levels caused by vasopressin. The results provide evidence for a role of c-fos expression in the maintenance of ethanol tolerance by vasopressin.