Tuesday, January 19, 2016 1:04:23 PM
http://www.ncbi.nlm.nih.gov/pubmed/26049209
>>> Biol Psychiatry. 2015 May 2. pii: S0006-3223(15)00357-1. doi: 10.1016/j.biopsych.2015.04.019. [Epub ahead of print]
Naltrexone Facilitates Learning and Delays Extinction by Increasing AMPA Receptor Phosphorylation and Membrane Insertion.
Kibaly C1, Kam AY2, Loh HH2, Law PY2.
Abstract
BACKGROUND:
The opioid antagonists naloxone/naltrexone are involved in improving learning and memory, but their cellular and molecular mechanisms remain unknown. We investigated the effect of naloxone/naltrexone on hippocampal a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) trafficking, a molecular substrate of learning and memory, as a probable mechanism for the antagonists activity.
METHODS:
To measure naloxone/naltrexone-regulated AMPAR trafficking, pHluorin-glutamate A1 (GluA1) imaging and biochemical analyses were performed on primary hippocampal neurons. To establish the in vivo role of GluA1-Serine 845 (S845) phosphorylation on the behavioral effect induced by inhibition of the endogenous µ-opioid receptor (MOR) by naltrexone, MOR knockout, and GluA1-S845A mutant (in which Ser845 was mutated to Ala) mice were tested in a water maze after chronic naltrexone administration. Behavioral responses and GluA1 levels in the hippocampal postsynaptic density in wild-type and GluA1-S845A mutant mice were compared using Western blot analysis.
RESULTS:
In vitro prolonged naloxone/naltrexone exposure significantly increased synaptic and extrasynaptic GluA1 membrane expression as well as GluA1-S845 phosphorylation. In the MOR knockout and GluA1-S845A mutant mice, naltrexone did not improve learning, which suggests that naltrexone acts via inhibition of endogenous MOR action and alteration of GluA1 phosphorylation. Naltrexone-treated wild-type mice had significantly increased phosphorylated GluA1-S845 and GluA1 levels in their hippocampal postsynaptic density on the third day of acquisition, which is the time when naltrexone significantly improved learning.
CONCLUSIONS:
The beneficial effect of naltrexone on spatial learning and memory under normal conditions appears to be the result of increasing GluA1-S845 phosphorylation-dependent AMPAR trafficking. These results can be further explored in a mouse model of memory loss.
Published by Elsevier Inc.
KEYWORDS:
AMPA receptors; GluA1; GluA1-S845; GluA1-S845A mutant; Naltrexone; Spatial memory
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