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

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 (0.5 mg/kg) or vehicle during withdrawal, 30 h 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.