Prenatal alcohol exposure can produce central nervous system dysfunction, resulting in a wide range of behavioral alterations. The mechanisms by which ethanol disrupts brain and behavioral development, however are currently unknown. Preliminary data demonstrate that administration of MK-801, a noncompetitive NMDA receptor antagonist, during ethanol withdrawal in neonatal rats can attenuate ethanol-induced deficits on a spatial discrimination reversal task. These results suggest that withdrawal-related NMDA receptor-mediated excitotoxicity may be one mechanism producing alcohol's adverse effects on behavioral development. This project proposes to investigate the factors that determine the effectiveness of MK-801 in mitigating ethanol induced behavioral alterations. Rat pups are exposed to ethanol during the neonatal brain growth spurt, a period of development equivalent to a portion of the human's third trimester in utero, via an artificial rearing procedure. MK-801 is administered during withdrawal and behavioral performance is examined with two behavioral tasks: open field activity and serial spatial discrimination reversal learning. These two tasks are sensitive to early alcohol exposure and are believed to rely on the functional integrity of the hippocampus, an area sensitive to both neonatal ethanol exposure and NMDA receptor-related excitotoxicity. Preliminary evidence suggests that MK-801 can either exacerbate or protect against ethanol-related teratogenic effects, depending on the dose and timing of administration. Thus, the dose-response and time course of the effects of MK-801 are evaluated to determine the parameters that control the interaction of ethanol and MK-801. Secondly, given that chronic ethanol treatment has been shown to produce a greater upregulation of NMDA receptors, the comparative effects of MK-801 following acute vs. chronic ethanol exposure is examined. Finally, a preliminary exploration into the effects of postnatal ethanol and MK-801 administration on hippocampal neuropathology is conducted. Characterization of the behavioral consequences of blocking NMDA receptors during developmental ethanol withdrawal lays an important foundation for future studies on the role of withdrawal-related neurotoxicity in fetal alcohol effects.
| Thomas, J D; Leany, B D; Riley, E P (2003) Differential vulnerability to motor deficits in second replicate HAS and LAS rats following neonatal alcohol exposure. Pharmacol Biochem Behav 75:17-24 |
| Thomas, Jennifer D; Fleming, S L; Riley, E P (2002) Administration of low doses of MK-801 during ethanol withdrawal in the developing rat pup attenuates alcohol's teratogenic effects. Alcohol Clin Exp Res 26:1307-13 |
| Thomas, J D; Fleming And, S L; Riley, E P (2001) MK-801 can exacerbate or attenuate behavioral alterations associated with neonatal alcohol exposure in the rat, depending on the timing of administration. Alcohol Clin Exp Res 25:764-73 |
| Thomas, J D; Riley, E P (1998) Fetal alcohol syndrome: does alcohol withdrawal play a role? Alcohol Health Res World 22:47-53 |
