MK-801 can exacerbate or attenuate behavioral alterations associated with neonatal alcohol exposure in the rat, depending on the timing of administration

Background: We have reported that administration of MK-801, an NMDA recepto r antagonist, during ethanol withdrawal in the developing rat attenuates et hanol's adverse effects on behavioral development. In the present study, we altered the timing of MK-801 delivery in relation to the last alcohol dose to determine if its protective effects were specific to the ethanol withdr awal phase. Methods: Five groups of rats were artificially reared and exposed to alcoho l in a binge-like manner on postnatal day (PD) 6, producing peak blood alco hol levels of 335 mg/dl that cleared to 0 mg/dl by 33 hours. Four groups re ceived MK-801 at various times after alcohol treatment (0, 9, 21, or 33 hr post-ethanol). The fifth alcohol-treated group received saline. Two artific ially reared control groups were included: one was injected with saline and the other injected with 0.5 mg/kg MK-801. Finally, a normally reared suckl e control group was also included. Activity level and performance on a spat ial discrimination reversal-learning task were evaluated at PD 18 and PD 40 , respectively. Results: Administration of MK-801 at the same time as ethanol treatment (0 hr) produced a high rate of mortality. Ethanol exposure on PD6 increased ac tivity level relative to controls. Administration of MK-801 at 0 hr exacerb ated this ethanol-induced overactivity, whereas administration of MK-801 at 21 and 33 hr reduced the severity of ethanol-related overactivity. Similar ly, ethanol exposure on PB 6 significantly increased the number of errors c ommitted on a spatial discrimination reversal-learning task. MK-801 injecti ons 9 hrs after ethanol exacerbated this effect, whereas MK-801 treatment 3 3 hrs after ethanol attenuated this effect. Thus, MK-801 administration at the time of ethanol treatment was highly toxic, whereas during the withdraw al period it was protective. Conclusion: These data are consistent with the hypothesis that ethanol expo sure in the neonatal rat inhibits the NMDA receptor, producing a subsequent rebound in NMDA receptor activation and possible excitotoxicity during wit hdrawal. Both the acute inhibitory effects of ethanol and the: excitatory E ffects of withdrawal may contribute to fetal alcohol effects.