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Molecular Pharmacology

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Research ArticleArticle

Chronic Intermittent Ethanol Treatment Selectively Alters N-Methyl-d-aspartate Receptor Subunit Surface Expression in Cultured Cortical Neurons

Mei Qiang, Ashley D. Denny and Maharaj K. Ticku
Molecular Pharmacology July 2007, 72 (1) 95-102; DOI: https://doi.org/10.1124/mol.106.033043
Mei Qiang
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Ashley D. Denny
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Maharaj K. Ticku
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Abstract

A chronic intermittent ethanol (CIE) exposure regimen consists of repeated episodes of ethanol intoxication and withdrawal. CIE treatment has been reported to result in a significant enhancement of N-methyl-d-aspartate (NMDA) receptor-mediated synaptic responses in vivo, and trafficking of NMDA receptors is emerging a key regulatory mechanism that underlies the channel function. Therefore, in the present study, we examined the effects of CIE on NMDA receptor subunit surface expression. Cultured cortical neurons were exposed to 75 mM ethanol for 14 h followed by 10 h of withdrawal, repeated this cycle five times, and followed by 2 or 5 days of withdrawal. Surface-expressed NMDA receptor subunits and their endocytosis were measured by biotinylation and Western blots. CIE significantly increased NMDA receptor (NR) 1 and NR2B but not NR2A subunit surface expression after 5 days of treatment. However, CIE treatment did not reduce the NMDA receptor endocytosis. Quantification of immunocytochemistry confirmed CIE-induced increase in both the total number of NR1 and NR2B subunit clusters and their targeting to synaptic sites. It is noteworthy that this effect persisted even after ethanol withdrawal with a peak expression occurring between 0 and 2 days after withdrawal, and the expression on the plasma membrane was still at high levels after 5 days of withdrawal. In addition, this was accompanied by significant increases in postsynaptic density protein 95 clusters. Protein kinase A inhibitor completely reversed CIE-induced increase in NR1 and partially in NR2B surface level and a long-lasting effect. These changes may contribute to the development of ethanol-induced neurotoxicity and ethanol dependence.

Footnotes

  • This work was supported by National Institute on Alcohol Abuse and Alcoholism grant AA12297 (to M.K.T.).

  • ABBREVIATIONS: NMDA, N-methyl-d-aspartate; CIE, chronic intermittent ethanol; DIV, days in vitro; NR, N-methyl-d-aspartate receptor; PSD 95, postsynaptic density protein 95; PKA, protein kinase A; PBS, phosphate-buffered saline; Ctl, control; MK-801, 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); KT-5720, (9α,10β,12α)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo(1,2,3-fg: 3′,2′,1′-kl)pyrrolo (3,4-i)(1,6)benzodiazocine-10-carboxylic acid, hexyl ester.

    • Received November 27, 2006.
    • Accepted April 17, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (1)
Molecular Pharmacology
Vol. 72, Issue 1
1 Jul 2007
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Research ArticleArticle

Chronic Intermittent Ethanol Treatment Selectively Alters N-Methyl-d-aspartate Receptor Subunit Surface Expression in Cultured Cortical Neurons

Mei Qiang, Ashley D. Denny and Maharaj K. Ticku
Molecular Pharmacology July 1, 2007, 72 (1) 95-102; DOI: https://doi.org/10.1124/mol.106.033043

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Research ArticleArticle

Chronic Intermittent Ethanol Treatment Selectively Alters N-Methyl-d-aspartate Receptor Subunit Surface Expression in Cultured Cortical Neurons

Mei Qiang, Ashley D. Denny and Maharaj K. Ticku
Molecular Pharmacology July 1, 2007, 72 (1) 95-102; DOI: https://doi.org/10.1124/mol.106.033043
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