Role of major NMDA or AMPA receptor subunits in MK-801 potentiation of ethanol intoxication

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.
Alcoholism Clinical and Experimental Research (Impact Factor: 3.31). 07/2008; 32(8):1479-92. DOI: 10.1111/j.1530-0277.2008.00715.x
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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    • "Males and females were used. GluN2A KO mice were generated as previously described and have a constitutive deletion of GluN2A [34] [35] [36] [37] [38]. The mutant line was backcrossed onto a C57BL/6J background for >10 generations. "
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    • "In behavioral studies, the NR2 knock-out induces locomotor incoordination and prevents mice from developing place preference following conditioning with ethanol injections (Boyce- Rustay and Holmes 2006). The NR2A knock-out animals also showed reduced sedation resulting from an interaction between ethanol and MK-801 (Palachick et al. 2008). Although there are strong implications for the necessity of the NR1, NR2A, and NR2B subunits, these findings cannot conclusively link one NMDAR site to the effects of ethanol. "
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    • "In our experiments, D-serine was able to reduce initial ethanol sensitivity at the two highest concentrations and to hasten acute tolerance at the maximum dose in sedation tests. The saline control values we obtained were consistent with other reports using the same mouse strain and ethanol concentration (Palachick et al., 2008). The ameliorative effects of D-serine were only observed when the drug was administered 15 min before ethanol (or up to 60 min prior in our preliminary tests, data not shown). "
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