TY - JOUR T1 - Aberrant Synaptic Activation of <em>N</em>-Methyl-<span class="sc">d</span>-aspartate Receptors Underlies Ethanol Withdrawal Hyperexcitability JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 60 LP - 72 DO - 10.1124/jpet.106.111419 VL - 321 IS - 1 AU - Adam W. Hendricson AU - Regina E. Maldve AU - Armando G. Salinas AU - Jonathan W. Theile AU - Tao A. Zhang AU - Laurea M. Diaz AU - Richard A. Morrisett Y1 - 2007/04/01 UR - http://jpet.aspetjournals.org/content/321/1/60.abstract N2 - 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 α-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. The American Society for Pharmacology and Experimental Therapeutics ER -