title: Increased small conductance calcium-activated potassium type 2 channel-mediated negative feedback on N-methyl-D-aspartate receptors impairs synaptic plasticity following context-dependent sensitization to morphine.
abstract: BACKGROUND
  Hippocampal long-term potentiation (LTP) is impaired following repeated morphine administration paired with a novel context. This procedure produces locomotor sensitization that can be abolished by blocking calcium (Ca(2+))-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) in the hippocampus. However, the mechanisms underlying LTP impairment remain unclear. Here, we investigate the role of N-methyl-D-aspartate receptors (NMDARs), AMPARs, and small conductance Ca(2+)-activated potassium type 2 (SK2) channels in LTP induction after context-dependent sensitization to morphine.
  
  
  METHODS
  Mice were treated with saline or escalating doses of morphine (5, 8, 10, and 15 mg/kg) every 12 hours in a locomotor activity chamber and a challenge dose of 5 mg/kg morphine was given 1 week later. After the challenge, the hippocampi were removed to assay phosphatase 2A (PP2A) activity, NMDAR, and SK2 channel synaptic expression or to perform electrophysiological recordings.
  
  
  RESULTS
  Impaired hippocampal LTP, which accompanied morphine-induced context-dependent sensitization, could not be restored by blocking Ca(2+)-permeable AMPARs. Context-dependent sensitization to morphine altered hippocampal NMDAR subunit composition and enhanced the SK2 channel-mediated negative feedback on NMDAR. Increased PP2A activity observed following context-dependent sensitization suggests that the potentiated SK2 channel effect on NMDAR was mediated by increased SK2 sensitivity to Ca(2+). Finally, inhibition of SK2 channel or PP2A activity restored LTP.
  
  
  CONCLUSIONS
  Our studies demonstrate that the SK2 channel-NMDAR feedback loop plays a role in opiate-induced impairment of hippocampal plasticity and that the positive modulation of SK2 channels occurs via increases in PP2A activity. This provides further evidence that small conductance Ca(2+)-activated potassium channels play a role in drug-induced plasticity.
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Fakira
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York.
authors.forename: George S
authors.initials: GS
authors.lastname: Portugal
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York.
authors.forename: Brianna
authors.initials: B
authors.lastname: Carusillo
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York.
authors.forename: Zare
authors.initials: Z
authors.lastname: Melyan
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York. Electronic address: jm3473@columbia.edu.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Morón
mesh_terms: D000818:Animals; D001030:Apamin / Q000494:pharmacology; D059333:Central Nervous System Sensitization / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D025461:Feedback, Physiological / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D019319:Okadaic Acid / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D021122:Protein Subunits / Q000378:metabolism; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D055366:Synaptic Potentials / Q000187:drug effects / Q000502:physiology
chemical_list: C496898:Kcnn2 protein, mouse; D021122:Protein Subunits; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D051640:Small-Conductance Calcium-Activated Potassium Channels; C067506:1-naphthylacetylspermine; D019319:Okadaic Acid; D001030:Apamin; D013096:Spermine; D009020:Morphine; D054648:Protein Phosphatase 2
keywords: Apamin; PP2A; SK2-NMDA loop; hippocampus; locomotor activity; long-term potentiation