MK-801 administration during ethanol withdrawal in neonatal rat pups attenuates ethanol-induced behavioral deficits.
Alcohol exposure during development can produce central nervous system dysfunction, resulting in a wide range of behavioral alterations. The various mechanisms by which alcohol causes these behavioral changes, however, remain unknown. One mechanism that has been suggested is NMDA receptor-mediated excitotoxic cell death produced by ethanol withdrawal. The present study examined whether MK-801, an antagonist of the NMDA receptor that has been shown to protect against NMDA receptor-mediated excitotoxicity, could block alcohol's adverse effects on behavior. Sprague-Dawley rat pups were exposed to alcohol (6.0 g/kg) in a binge-like manner on postnatal day 6 using an artificial rearing procedure. Subjects then received an injection of MK-801 (0.1 mg/kg) or vehicle during withdrawal, 21 hr after ethanol exposure. At postnatal day 40, all subjects were tested on a serial spatial discrimination reversal task. Ethanol-exposed subjects were impaired in both discrimination and reversal learning, and committed a significantly greater number of perseverative-type errors, compared with controls. MK-801 administration during ethanol withdrawal significantly attenuated ethanol-induced deficits in reversal learning and increases in perseverative-type errors, whereas MK-801 exposure by itself had no significant effect on performance. Thus, exposure to MK-801 during ethanol withdrawal partially protected against alcohol-related disruptions in spatial reversal learning. These results support the suggestion that NMDA receptor-mediated excitotoxicity may be one mechanism by which alcohol induces behavioral teratogenicity.
Thomas
J D
JD
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California, USA.
Weinert
S P
SP
Sharif
S
S
Riley
E P
EP
D000430:Alcohol Withdrawal Delirium / Q000503:physiopathology*; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000503:physiopathology*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D011939:Mental Recall / Q000187:drug effects / Q000502:physiology; D009357:Neonatal Abstinence Syndrome / Q000503:physiopathology*; D009949:Orientation / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology; D012193:Reversal Learning / Q000187:drug effects / Q000502:physiology
D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate