Fakira Amanda K, Portugal George S, Carusillo Brianna, Melyan Zare, Morón Jose A
Department of Anesthesiology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York.
Department of Anesthesiology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York.
Biol Psychiatry. 2014 Jan 15;75(2):105-14. doi: 10.1016/j.biopsych.2013.04.026. Epub 2013 Jun 2.
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.
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.
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.
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.
在与新环境配对的反复吗啡给药后，海马体长期增强效应（LTP）受损。此过程会产生运动敏化，而通过阻断海马体中钙（Ca(2+)）通透的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPARs）可消除该运动敏化。然而，LTP受损背后的机制仍不清楚。在此，我们研究N-甲基-D-天冬氨酸受体（NMDARs）、AMPARs和小电导Ca(2+)激活钾通道2型（SK2）在吗啡情境依赖性敏化后LTP诱导中的作用。
在运动活动箱中，每12小时给小鼠注射生理盐水或递增剂量的吗啡（5、8、10和15mg/kg），1周后给予5mg/kg吗啡的激发剂量。激发后，取出海马体以检测磷酸酶2A（PP2A）活性、NMDAR和SK2通道的突触表达，或进行电生理记录。
伴随吗啡诱导的情境依赖性敏化的海马体LTP受损，无法通过阻断Ca(2+)通透的AMPARs来恢复。吗啡的情境依赖性敏化改变了海马体NMDAR亚基组成，并增强了SK2通道对NMDAR的负反馈。情境依赖性敏化后观察到的PP2A活性增加表明，SK2通道对NMDAR的增强作用是由SK2对Ca(2+)敏感性增加介导的。最后，抑制SK2通道或PP2A活性可恢复LTP。
我们的研究表明，SK2通道-NMDAR反馈回路在阿片类药物诱导的海马体可塑性损伤中起作用，且SK2通道的正向调节是通过PP2A活性增加实现的。这进一步证明了小电导Ca(2+)激活钾通道在药物诱导的可塑性中起作用。
