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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 17, 2007; DOI: 10.1124/jpet.106.111419

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Received for publication July 24, 2006.
Revised January 12, 2007.
Accepted for publication January 16, 2007.

Aberrant Synaptic Activation of NMDA Receptors Underlies Ethanol Withdrawal Hyperexcitability

Adam W. Hendricson 1, Regina E. Maldve 1, Armando G. Salinas 1, Jon W. Theile 1, Tao A. Zhang 1, Laurea M. Diaz 1, Richard A. Morrisett 2*

1 Univ Texas-Austin 2 University of Texas at Austin

* Address correspondence to: E-mail: ramorris{at}mail.utexas.edu

Abstract

Chronic ethanol exposure may induce neuroadaptive responses in NMDA receptors which are thought to underlie a variety of alcohol-related brain disorders. Here, we demonstrate that hyperexcitability triggered by withdrawal (WD) from chronic ethanol exposure is associated with increases in both synaptic NMDA receptor expression and activation. Withdrawal from chronic ethanol exposure (75 mM ethanol, 5-9 days) elicited robust and prolonged epileptiform activity in CA1 pyramidal neurons from hippocampal explants which was absolutely dependent upon NMDA receptor activation but independent of chronic inhibition of PKA. Analysis of Sr++-supported asynchronous NMDA receptor-mediated mEPSCs was employed to assess changes in NMDA neurotransmission. Following chronic exposure, ethanol withdrawal was associated with an increase in mEPSC amplitude 3.38-fold over that following withdrawal from acute ethanol exposure. Analysis of paired evoked AMPA EPSCs and spontaneous mEPSCs indicated that withdrawal following chronic exposure was also associated with a selective increase in action potential evoked but not spontaneous transmitter release probability. Immunoblot analysis revealed significant increases in total NR1, NR2A and NR2B subunit expression following chronic exposure and unaffected by PKA-inhibition manner. Confocal imaging studies indicate that increased NR1 subunit expression was associated with increased density of NR1 expression on dendrites in parallel with a selective increase in the size of NR1 puncta on dendritic spines. Therefore, neuroadaptation to chronic ethanol exposure in NMDA synaptic transmission is responsible for aberrant network excitability following withdrawal and result from changes in both postsynaptic function as well as presynaptic release.


Key words: depressant, glutamate, organotypic, plasticity, seizure, trafficking


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