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First published on April 17, 2007; DOI: 10.1124/mol.106.033043

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Received for publication November 28, 2006.
Revised March 9, 2007.
Accepted for publication April 17, 2007.

Chronic Intermittent Ethanol Treatment Selectively Alters NMDA Receptor Subunits Surface Expression in Cultured Cortical Neurons

Mei Qiang 1*, Ashley D Denny 1, Maharaj K. Ticku 2

1 The University of Texas Health Science Center at San Antonio 2 University of Texas Health Science Center

* Address correspondence to: E-mail: qiang{at}uthscsa.edu

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 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 withdrawal, repeated this cycle 5 times and followed by 2 or 5 days withdrawal. Surface-expressed NMDA receptor subunits and their endocytosis were measured by biotinylation and Western blots. CIE significantly increased NR1 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. Importantly, this effect persisted even following ethanol withdrawal with a peak expression occurring between 0-2 day 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 PSD 95 clusters. PKA inhibitor completely reversed CIE-induced increase in NR1 and partially in NR2B surface level as well as long lasting effect. These changes may contribute to the development of ethanol-induced neurotoxicity and ethanol dependence.


Key words: Glutamate, Protein Kinase A, Alcohol, Drug tolerance/dependence


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