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Ethanol withdrawal hyper‐responsiveness mediated by NMDA receptors in spinal cord motor neurons
Author(s) -
Li HuiFang,
Kendig Joan J
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705198
Subject(s) - nmda receptor , ampa receptor , washout , excitatory postsynaptic potential , glutamate receptor , spinal cord , chemistry , electrophysiology , medicine , neuroscience , endocrinology , anesthesia , pharmacology , receptor , biology
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. 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). 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. 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. 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, P <0.001). When NMDA applications were stopped durithe period of EtOH exposure, mean area of NMDA‐evoked responses on washout was only 98.0±5% of control ( n =6, P >0.05). The tyrosine kinase inhibitor genistein (10–20 μ M ) 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. The protein kinase A (PKA) inhibitor Rp‐cAMP (20–500 μ M ) did not block withdrawal hyper‐responsiveness. On washout, the mean NMDA‐evoked current area was 124±6% of control ( n =5, P <0.05). Two broad‐spectrum specific protein kinase C (PKC) inhibitors, GF‐109203X (0.3 μ M ) and chelerythrine chloride (0.5–2 n M ), blocked withdrawal hyper‐responsiveness. Responses on washout were 108±7%, n =5 and 88±4%, n =4 of control, respectively, P >0.05. 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.British Journal of Pharmacology (2003) 139 , 73–80. doi: 10.1038/sj.bjp.0705198