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Published on: July 13, 2014
Administration of eliprodil during ethanol withdrawal in the neonatal rat attenuates ethanol-induced learning
J D Thomas1, G G Garcia, H D Dominguez
1Center for Behavioral Teratology, Department of Psychology, San Diego State University, 6363 Alvarado Ct., Ste. 209, San Diego, CA 92120, USA. thomas3@mail.sdsu.edu
Rationale:
Prenatal exposure to alcohol can disrupt brain development, leading to a variety of behavioral alterations, including learning deficits. We have postulated that some central nervous system damage may be due to N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity that occurs during ethanol withdrawal. Consistent with this hypothesis, we previously demonstrated that administration of MK-801, an NMDA receptor antagonist, during ethanol withdrawal attenuates ethanol-related learning deficits using an animal model of fetal alcohol effects. However, MK-801 binds to the phencyclidine site, which affects all NMDA receptor subtypes and can cause adverse side effects and toxicity. Eliprodil is a more selective NMDA receptor antagonist that acts at the polyamine modulatory site of NMDA receptors.
Objectives:
The purpose of this study was to determine if administration of eliprodil during ethanol withdrawal would reduce the severity of learning deficits associated with developmental alcohol exposure.
Methods:
Male rat pups were randomly assigned to ethanol-exposed or control treatments. On postnatal day (PD) 6, during a period of brain development similar to that of the mid-third trimester in humans, subjects were exposed to 6.0 g/kg ethanol or isocaloric maltose solutions via oral gavage. Twenty-four hours after the end of the ethanol treatment, during ethanol withdrawal, all subjects received an intraperitoneal injection of one of three doses of eliprodil (5, 10, or 25 mg/kg) or vehicle. On PD 40, all subjects were tested on a serial spatial discrimination reversal learning task.
Results:
Ethanol-exposed subjects treated with vehicle committed a significantly greater number of errors compared to controls. Administration of eliprodil during ethanol withdrawal significantly decreased the number of errors in the ethanol-exposed groups, but had no significant effect on the performance of controls.
Conclusion:
These data support the hypothesis that NMDA receptor-mediated excitotoxicity during ethanol withdrawal contributes to fetal alcohol effects.
