AKAP signaling in reinstated cocaine seeking revealed by iTRAQ proteomic analysis.
AKAP signaling in reinstated cocaine seeking revealed by iTRAQ proteomic analysis.
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DOI：
10.1523/jneurosci.3452-10.2011
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发表时间：
2011-04-13
期刊：
影响因子：
--
通讯作者：
Kalivas PW
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文献类型：
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作者：
Reissner KJ;Uys JD;Schwacke JH;Comte-Walters S;Rutherford-Bethard JL;Dunn TE;Blumer JB;Schey KL;Kalivas PW
In order to identify candidate proteins in the nucleus accumbens (NAc) as potential pharmacotherapeutic targets for treating cocaine addition, an 8-plex iTRAQ proteomic screen was performed using NAc tissue obtained from rats trained to self-administer cocaine followed by extinction training. Compared to yoked-saline controls, 42 proteins in a postsynaptic density (PSD)-enriched subfraction of the NAc from cocaine-trained animals were identified as significantly changed. Among proteins of interest whose levels were identified as increased was AKAP79/150, the rat ortholog of human AKAP5, a PSD scaffolding protein that localizes signaling molecules to the synapse. Functional down-regulation of AKAP79/150 by microinjecting a cell-permeable synthetic AKAP peptide into the NAc in order to disrupt AKAP-dependent signaling revealed that inhibition of AKAP signaling impaired the reinstatement of cocaine-seeking. Reinstatement of cocaine-seeking is thought to require upregulated surface expression of AMPA glutamate receptors, and the inhibitory AKAP peptide reduced the PSD content of PKA as well as surface expression of GluR1 in NAc. However, reduced surface expression was not associated with changes in PKA phosphorylation of GluR1. This series of experiments demonstrates that proteomic analysis provides a useful tool for identifying proteins that can regulate cocaine relapse, and that AKAP proteins may contribute to relapse vulnerability by promoting increased surface expression of AMPA receptors in the NAc.
