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Administration of eliprodil during ethanol withdrawal in the neonatal rat attenuates ethanol-induced learning deficits

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Abstract

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.

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Acknowledgements

This study was supported by NIAAA Grant AA06902.

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Authors and Affiliations

  1. Center for Behavioral Teratology, Department of Psychology, San Diego State University, 6363 Alvarado Ct., Ste. 209, San Diego, CA 92120, USA

    J. D. Thomas, G. G. Garcia, H. D. Dominguez & E. P. Riley

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  1. J. D. Thomas
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  2. G. G. Garcia
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  3. H. D. Dominguez
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  4. E. P. Riley
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Correspondence to J. D. Thomas.

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Thomas, J.D., Garcia, G.G., Dominguez, H.D. et al. Administration of eliprodil during ethanol withdrawal in the neonatal rat attenuates ethanol-induced learning deficits. Psychopharmacology 175, 189–195 (2004). https://doi.org/10.1007/s00213-004-1806-x

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