QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.111419v1 321/1/60    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hendricson, A. W. Articles by Morrisett, R. A. Search for Related Content PubMed PubMed Citation Articles by Hendricson, A. W. Articles by Morrisett, R. A.

NEUROPHARMACOLOGY

Aberrant Synaptic Activation of N-Methyl-D-aspartate Receptors Underlies Ethanol Withdrawal Hyperexcitability

Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, Texas

Chronic ethanol exposure may induce neuroadaptive responses in N-methyl-D-aspartate (NMDA) receptors, which are thought to underlie a variety of alcohol-related brain disorders. Here, we demonstrate that hyperexcitability triggered by withdrawal 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 protein kinase A (PKA). Analysis of Sr²⁺-supported asynchronous NMDA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) was employed to assess changes in NMDA neurotransmission. After chronic exposure, ethanol withdrawal was associated with an increase in mEPSC amplitude 3.38-fold over that after withdrawal from acute ethanol exposure. Analysis of paired evoked -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid EPSCs and spontaneous mEPSCs indicated that withdrawal after 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 after 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 after withdrawal and results from changes in both postsynaptic function as well as presynaptic release.

Address correspondence to: Dr. Richard A. Morrisett, University of Texas at Austin, PHAR-Pharmacology, 1 University Station A1915, Austin, TX 78712-0125. E-mail: ramorris{at}mail.utexas.edu

This article has been cited by other articles:

				P. J. Mulholland, E. P. Carpenter-Hyland, M. C. Hearing, H. C. Becker, J. J. Woodward, and L. J. Chandler Glutamate Transporters Regulate Extrasynaptic NMDA Receptor Modulation of Kv2.1 Potassium Channels J. Neurosci., August 27, 2008; 28(35): 8801 - 8809. [Abstract] [Full Text] [PDF]