title: GABA transporter currents activated by protein kinase A excite midbrain neurons during opioid withdrawal.
abstract: Adaptations in neurons of the midbrain periaqueductal gray (PAG) induced by chronic morphine treatment mediate expression of many signs of opioid withdrawal. The abnormally elevated action potential rate of opioid-sensitive PAG neurons is a likely cellular mechanism for withdrawal expression. We report here that opioid withdrawal in vitro induced an opioid-sensitive cation current that was mediated by the GABA transporter-1 (GAT-1) and required activation of protein kinase A (PKA) for its expression. Inhibition of GAT-1 or PKA also prevented withdrawal-induced hyperexcitation of PAG neurons. Our findings indicate that GAT-1 currents can directly increase the action potential rates of neurons and that GAT-1 may be a target for therapy to alleviate opioid-withdrawal symptoms.
authors.affiliation: Pain Management Research Institute at Royal North Shore Hospital, The University of Sydney, NSW 2006, Australia. bagleye@med.usyd.edu.au
authors.forename: Elena E
authors.initials: EE
authors.lastname: Bagley
authors.forename: Michelle B
authors.initials: MB
authors.lastname: Gerke
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Vaughan
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hack
authors.forename: MacDonald J
authors.initials: MJ
authors.lastname: Christie
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology; D000818:Animals; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins; D008297:Male; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009293:Opioid-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D009924:Organ Culture Techniques; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018118:Chloride Channels; D004791:Enzyme Inhibitors; D050485:GABA Plasma Membrane Transport Proteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; C493414:Slc6a1 protein, mouse; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D017868:Cyclic AMP-Dependent Protein Kinases