Role of major NMDA or AMPA receptor subunits in MK-801 potentiation of ethanol intoxication.
BACKGROUND
The glutamate system plays a major role in mediating EtOH's effects on brain and behavior, and is implicated in the pathophysiology of alcohol-related disorders. N-methyl-D-aspartate receptor (NMDAR) antagonists such as MK-801 (dizocilpine) interact with EtOH at the behavioral level, but the molecular basis of this interaction is unclear.


METHODS
We first characterized the effects of MK-801 treatment on responses to the ataxic (accelerating rotarod), hypothermic and sedative/hypnotic effects of acute EtOH administration in C57BL/6J and 129/SvImJ inbred mice. Effects of another NMDAR antagonist, phencyclidine, on EtOH-induced sedation/hypnosis were also assessed. Gene knockout of the NMDAR subunit NR2A or l-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate GluR1 or pharmacological antagonism of the NMDAR subunit NR2B (via Ro 25-6981) was employed to examine whether inactivating any one of these glutamate signaling molecules modified MK-801's effect on EtOH-related behaviors.


RESULTS
MK-801 markedly potentiated the ataxic effects of 1.75 g/kg EtOH and the sedative/hypnotic effects of 3.0 g/kg EtOH, but not the hypothermic effects of 3.0 g/kg EtOH, in C57BL/6J and 129/SvImJ mice. Phencyclidine potentiated EtOH-induced sedation/hypnosis in both inbred strains. Neither NR2A nor GluR1 KO significantly altered basal EtOH-induced ataxia, hypothermia, or sedation/hypnosis. Ro 25-6981 modestly increased EtOH-induced sedation/hypnosis. The ability of MK-801 to potentiate EtOH-induced ataxia and sedation/hypnosis was unaffected by GluR1 KO or NR2B antagonism. NR2A KO partially reduced MK-801 + EtOH-induced sedation/hypnosis, but not ataxia or hypothermia.


CONCLUSIONS
Data confirm a robust and response-specific potentiating effect of MK-801 on sensitivity to EtOH's intoxicating effects. Inactivation of three major components of glutamate signaling had no or only partial impact on the ability of MK-801 to potentiate behavioral sensitivity to EtOH. Further work to elucidate the mechanisms underlying NMDAR x EtOH interactions could ultimately provide novel insight into the role of NMDARs in alcoholism and its treatment.
Palachick
Benjamin
B
Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, 5625 Fishers Lane Room 2N09, Rockville, MD 20852-9411, USA.
Chen
Yi-Chyan
YC
Enoch
Abigail J
AJ
Karlsson
Rose-Marie
RM
Mishina
Masayoshi
M
Holmes
Andrew
A
D000435:Alcoholic Intoxication / Q000503:physiopathology*; D000818:Animals; D001259:Ataxia / Q000139:chemically induced / Q000503:physiopathology; D002492:Central Nervous System Depressants / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004347:Drug Interactions; D000431:Ethanol / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D007035:Hypothermia / Q000139:chemically induced / Q000503:physiopathology; D046353:Immobility Response, Tonic / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010622:Phencyclidine / Q000494:pharmacology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D002492:Central Nervous System Depressants; D016291:Dizocilpine Maleate; D000431:Ethanol; D018696:Neuroprotective Agents; D010622:Phencyclidine; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C120997:NR2A NMDA receptor