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Biol Psychiatry. 2014 Jan 15;75(2):105-14. doi: 10.1016/j.biopsych.2013.04.026. Epub 2013 Jun 2.

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.

Author information

1
Department of Anesthesiology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York.
2
Department of Anesthesiology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York. Electronic address: jm3473@columbia.edu.

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.

KEYWORDS:

Apamin; PP2A; SK2-NMDA loop; hippocampus; locomotor activity; long-term potentiation

PMID:
23735878
PMCID:
PMC3992971
DOI:
10.1016/j.biopsych.2013.04.026
[Indexed for MEDLINE]
Free PMC Article

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