Inhibition of PKMζ 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-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 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.

Inhibiting PKMζ reveals dorsal lateral and dorsal medial striatum store the different memories needed to support adaptive behavior

“…Specifically, if endocytosis of the GluA2-containing AMPA receptors is prevented, then the temporary inactivation of PKMz should have no effect on memory maintenance because this renders the replacement function served by PKMz moot-no replacement is necessary. This hypothesis has been tested and supported in experiments with both brain slices and behavior Li et al 2011). Thus, we used this strategy to determine if our results with ZIP could be related, at least indirectly, to disrupting the role of PKMz in regulating trafficking of GluA2-containing AMPARs.…”

“…However, if it is infused at various intervals after LTP has been induced, established potentiation is reversed, indicating that PKMz is critical for the maintenance of established LTP. Second, when ZIP is injected into brain regions thought to be memory storage sites, behavioral evidence for the memory is lost (Pastalkova et al 2006;Shema et al 2007Shema et al , 2011Serrano et al 2008;Hardt et al 2010;Li et al 2011).…”

“…This view is supported by recent experiments that have combined the infusion of ZIP with an infusion of the peptide GluR2 3Y . This peptide has been shown to inhibit the endocytosis of GluA2-containing AMPARs Li et al 2011).…”

GluR2-3Y Inhibits the Acquisition and Reinstatement of Morphine-Induced Conditioned Place Preference in Rats

“…Then in which brain regions does GluR2-3Y inhibit the addictive behavior? Previous studies found that the endocytosis of AMPARs containing GluR2 in the NAc plays an important role in the expression of amphetamine-induced behavioral sensitization [21] and the long-term maintenance of mCPP [25]. Moreover, endocytosis in the BLA and in the ventral medial PFC is crucial for the reconsolidation of methamphetamine reward memory [26] and cue-induced heroin-seeking [15], respectively.…”

Addiction as an adaptation process in the brain, a view from neurobiology

“…However, recent exciting findings of erasure of memory traces by a selective antagonist of the protein kinase M zeta (Li et al, 2011;Sacktor, 2011;Shema, Sacktor, & Dudai, 2007) have increased the hope that permanently established neuronal connections could be reorganized later in life. Although these results have been questioned (Lisman, 2011;Volk, Bachman, Johnson, Yu, & Huganir, 2013;Wu-Zhang, Schramm, Nabavi, Malinow, & Newton, 2012), indicating that we do not understand the molecular mechanisms well enough, this line of research might turn out to be very fruitful for the future understanding of the memory-like processes that make compulsive addiction so persistent.…”