title: Inhibition of PKMzeta in nucleus accumbens core abolishes long-term drug reward memory.
abstract: During abstinence, memories of drug-associated cues persist for many months, 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 after CPP training blocked morphine CPP expression for up to 14 d after injections. This effect was mimicked by the PKC inhibitor chelerythrine, which inhibits PKMζ, 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-GluR2(3Y), 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 that PKMζ activity in accumbens core is a critical cellular substrate for the maintenance of memories of relapse-provoking reward cues during prolonged abstinence periods.
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Yan-qin
authors.initials: YQ
authors.lastname: Li
authors.forename: Yan-xue
authors.initials: YX
authors.lastname: Xue
authors.forename: Ying-ying
authors.initials: YY
authors.lastname: He
authors.forename: Fang-qiong
authors.initials: FQ
authors.lastname: Li
authors.forename: Li-fen
authors.initials: LF
authors.lastname: Xue
authors.forename: Chun-mei
authors.initials: CM
authors.lastname: Xu
authors.forename: Todd Charlton
authors.initials: TC
authors.lastname: Sacktor
authors.forename: Yavin
authors.initials: Y
authors.lastname: Shaham
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D009020:Morphine / Q000009:adverse effects; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000009:adverse effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000201:enzymology*; D009842:Oligopeptides / Q000494:pharmacology; D063065:Organophosphonates / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012201:Reward; D013375:Substance Withdrawal Syndrome / Q000201:enzymology / Q000503:physiopathology; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D009292:Narcotic Antagonists; D009294:Narcotics; D009842:Oligopeptides; D063065:Organophosphonates; D010879:Piperazines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C493869:carboxypiperazinyl propylphosphonic acid; C487010:myristoyl-seryl-leucyl-asparagyl-prolyl-glutamyl-tryptophyl-asparagyl-glutamyl-threonine; D009270:Naloxone; C056639:2-amino-5-phosphopentanoic acid; D009020:Morphine; D011493:Protein Kinase C; D014633:Valine; D003042:Cocaine