Repeated ethanol treatment in adolescent rats alters cortical NMDA receptor

Earlier we have reported that repeated ethanol treatment during adolescence causes long-lasting impairments in spatial learning and memory. The present study was undertaken to determine the cellular mechanisms underlying the persistent ethanol-induced cognitive dysfunction in adolescent male rats. Since in adult animals ethanol is known to affect the N-methyl-d-aspartate (NMDA) receptor–gated ion channel, the hypothesis tested here was that adolescent ethanol exposure modulates NMDA receptor (NR) regulation in the brain. Adolescent male rats were injected daily with ethanol (2 g/kg intraperitoneally) for 5 consecutive days. Control rats received isovolumetric saline for the same number of days. Groups of control and experimental rats were sacrificed 7 days after the last ethanol/saline administration, and NR activity was measured in specific brain regions (frontal cortex, hippocampus) using the [3H]MK-801 binding assay. In addition, some rats were sacrificed and their brains were used to investigate changes in NR pharmacology by measuring specific NR2 subunits immunohistochemically. Compared to saline-treated controls, ethanol-treated rats showed significant increases in [3H]MK-801 maximal binding in the frontal cortex. This was associated with increased cortical NR2B subunit protein. [3H]MK-801 binding in the hippocampus was minimally affected. These results indicate that ethanol exposure during the adolescent period produces brain region–specific alterations in NR activity. These changes are different from those reported in literature for ethanol administration during the perinatal period or adulthood. Together, these data suggest that adolescence represents a unique stage in brain development in its long-term sensitivity to ethanol.