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 receptor antagonist, during ethanol withdrawal in the developing rat attenuates ethanol'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 withdrawal phase.


METHODS
Five groups of rats were artificially reared and exposed to alcohol in a binge-like manner on postnatal day (PD) 6, producing peak blood alcohol levels of 335 mg/dl that cleared to 0 mg/dl by 33 hours. Four groups received MK-801 at various times after alcohol treatment (0, 9, 21, or 33 hr post-ethanol). The fifth alcohol-treated group received saline. Two artificially 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 suckle control group was also included. Activity level and performance on a spatial 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 activity level relative to controls. Administration of MK-801 at 0 hr exacerbated this ethanol-induced overactivity, whereas administration of MK-801 at 21 and 33 hr reduced the severity of ethanol-related overactivity. Similarly, ethanol exposure on PD 6 significantly increased the number of errors committed on a spatial discrimination reversal-learning task. MK-801 injections 9 hrs after ethanol exacerbated this effect, whereas MK-801 treatment 33 hrs after ethanol attenuated this effect. Thus, MK-801 administration at the time of ethanol treatment was highly toxic, whereas during the withdrawal period it was protective.


CONCLUSIONS
These data are consistent with the hypothesis that ethanol exposure in the neonatal rat inhibits the NMDA receptor, producing a subsequent rebound in NMDA receptor activation and possible excitotoxicity during withdrawal. Both the acute inhibitory effects of ethanol and the excitatory effects of withdrawal may contribute to fetal alcohol effects.
Thomas
J D
JD
Department of Psychology, Center for Behavioral Teratology, San Diego State University, San Diego, California 92120, USA. thomas3@mail.sdsu.edu
Fleming And
S L
SL
Riley
E P
EP
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000254:growth & development; D002492:Central Nervous System Depressants / Q000097:blood / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects* / Q000502:physiology; D016291:Dizocilpine Maleate / Q000008:administration & dosage*; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D005260:Female; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D002492:Central Nervous System Depressants; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D016291:Dizocilpine Maleate