MK-801 can exacerbate or attenuate behavioral alterations associated with neonatal alcohol exposure in the rat, depending on the timing of administration
Jd. Thomas et al., MK-801 can exacerbate or attenuate behavioral alterations associated with neonatal alcohol exposure in the rat, depending on the timing of administration, ALC CLIN EX, 25(5), 2001, pp. 764-773
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.