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- Title
Inhibition of PKMζ` in Nucleus Accumbens Core Abolishes Long-Term Drug Reward Memory.
- Authors
Yan-qin Li; Yan-xue Xue; Ying-ying He; Fang-qiong Li; Li-fen Xue; Chun-mei Xu; Sacktor, Todd Charlton; Shaham, Yavin; Lin Lu
- Abstract
During abstinence, memories of drug-associated cues persist formanymonths, and exposure to these cues often provokes relapse to drug use. The mechanisms underlying the maintenance of these memories are unknown. A constitutively active atypical protein kinase C (PKC) isozyme, protein kinase M ζ (PKMζ), is required for maintenance of spatial memory, conditioned taste aversion, and other memory forms. We used conditioned place preference (CPP) and conditioned place aversion (CPA) procedures to study the role of nucleus accumbens PKMζ in the maintenance of drug reward and aversion memories in rats. Morphine CPP training (10 mg/kg, 4 pairings) increased PKMζ levels in accumbens core but not shell. Injections of the PKMζ inhibitor ζ inhibitory peptide (ZIP) into accumbens core but not shell afterCPPtraining blocked morphineCPPexpression forupto 14 d after injections. This effect was mimicked by the PKC inhibitor chelerythrine, which inhibitsPKMζ, but not by the conventional and novel PKC inhibitor staurosporine, which does not effectively inhibit PKMζ. ZIP injections into accumbens core after training also blocked the expression of cocaine (10 mg/kg) and high-fat food CPP but had no effect on CPA induced by naloxone-precipitated morphine withdrawal. Accumbens core injections of Tat-GluR23Y, which inhibits GluR2-dependent AMPA receptor endocytosis, prevented the impairment in morphine CPP induced by local ZIP injections, indicating that the persistent effect of PKMζ is on GluR2-containing AMPA receptors. Results indicate thatPKMζ activity in accumbens core is a critical cellular substrate for the maintenance of memories of relapse-provoking reward cues during prolonged abstinence periods.
- Subjects
ISOENZYMES; FASTING; NUCLEUS accumbens; PROTEIN kinases; MORPHINE
- Publication
Journal of Neuroscience, 2011, Vol 31, Issue 14, p5436
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.5884-10.2011