MK-801 administration during neonatal ethanol withdrawal attenuates interpositus cell loss and juvenile eyeblink...

Binge-level doses of ethanol have been demonstrated to severely disrupt the cerebellum and cerebellum-dependent tasks when administered to rodent subjects during the early postnatal period. N-methyl-d-aspartic acid (NMDA) receptor-mediated excitotoxicity associated with ethanol withdrawal has been implicated as a significant component contributing to neurotoxic effects resulting from early ethanol exposure, and studies using MK-801 (dizocilpine) have reported protection from ethanol-induced damage. The present study examined whether the administration of MK-801 during ethanol withdrawal would ameliorate ethanol-associated cell death in the interpositus nucleus of the cerebellum and behavioral deficits in a cerebellar dependent task. Long Evans rat pups were treated with ethanol (5.25 g/kg) in a binge-like manner on postnatal day 6 using intragastric intubation. Subjects then received an injection of MK-801 (0.5mg/kg) or vehicle during withdrawal, 30h after ethanol exposure. Rats were then trained on an eyeblink classical conditioning task as juveniles (40 days of age), and cerebellar interpositus nucleus numbers were assessed after conditioning. Ethanol-exposed subjects exhibited reductions in neuronal populations and behavioral deficits during eyeblink conditioning. However, MK-801 administration significantly attenuated observed deficiencies, suggesting a protective effect resulting from MK-801 treatment during ethanol withdrawal. These results support the role of NMDA receptor-mediated excitotoxicity as a component mechanism by which ethanol produces teratogenicity. Additionally, our findings support previous reports that have shown correlations between dependent measures of eyeblink classical-conditioning behavior and unbiased cell counts in the interpositus nucleus.