Ethanol withdrawal hyper‐responsiveness mediated by NMDA receptors in spinal cord motor neurons

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Abstract
1. Following ethanol (EtOH) exposure, population excitatory postsynaptic potentials (pEPSPs) in isolated spinal cord increase to a level above control (withdrawal hyper-responsiveness). The present studies were designed to characterize this phenomenon and in particular to test the hypothesis that protein kinases mediate withdrawal. 2. Patch-clamp studies were carried out in motor neurons in rat spinal cord slices. Currents were evoked by brief pulses of glutamate, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartic acid (NMDA). 3. Of 15 EtOH-sensitive neurons in which currents were evoked by glutamate, four (27%) displayed withdrawal hyper-responsiveness in the washout period. Mean current area after washout was 129.6+/-5% of control. 4. When currents were evoked by AMPA, two of 10 neurons (20%) displayed withdrawal hyper-responsiveness, with a mean current area 122+/-8% of control on washout. 5. Of a group of 11 neurons in which currents were evoked by NMDA, nine (82%) displayed withdrawal hyper-responsiveness. Mean increase in current area at the end of the washout period was to 133+/-6% of control (n=9, P0.05). 6. The tyrosine kinase inhibitor genistein (10-20 microM) blocked withdrawal hyper-responsiveness. Of six EtOH-sensitive neurons, the mean NMDA-evoked current area after washout was 89+/-6% of control, P>0.05. 7 The protein kinase A (PKA) inhibitor Rp-cAMP (20-500 microM) did not block withdrawal hyper-responsiveness. On washout, the mean NMDA-evoked current area was 124+/-6% of control (n=5, P0.05. 9 NMDA activation during EtOH exposure is necessary for withdrawal hyper-responsiveness. Both tyrosine kinase and PKC, but not PKA, appear to be essential for EtOH withdrawal hyper-responsiveness mediated by postsynaptic NMDA receptors in spinal cord motor neurons.