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Updated: Mar 16, 2026
Quantifying Subcellular Ubiquitin-proteasome Activity in the Rodent Brain
Published on: May 21, 2019
Involvement of protein phosphatases in the destabilization of methamphetamine-associated contextual memory
Yang-Jung Yu1, Chien-Hsuan Huang1, Chih-Hua Chang1
1Institute of Basic Medical Sciences and Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan 701.
Abstract:
Destabilization refers to a memory that becomes unstable when reactivated and is susceptible to disruption by amnestic agents. Here we delineated the cellular mechanism underlying the destabilization of drug memory. Mice were conditioned with methamphetamine (MeAM) for 3 d, and drug memory was assessed with a conditioned place preference (CPP) protocol. Anisomycin (ANI) was administered 60 min after the CPP retrieval to disrupt reconsolidation. We found that destabilization of MeAM CPP after the application of ANI was blocked by the N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801 and the NR2B antagonist ifenprodil (IFN) but not by the NR2A antagonist NVP-AAM077 (NVP). In addition, decrease in the phosphorylation of GluR1 at Serine845 (p-GluR1-Ser845), decrease in spine density, and a reduction in the AMPAR/NMDAR ratio in the basolateral amygdala (BLA) were reversed after the MK-801 treatment. The effect of ANI on destabilization was prevented by the protein phosphatase 2B (calcineurin, CaN) inhibitors cyclosporine A (CsA) and FK-506 and the protein phosphatase 1 (PP1) inhibitors calyculin A (CA) and okadaic acid (OA). These results suggest that memory destabilization involves the activation of NR2B-containing NMDARs, which in turn allows the influx of Ca(2+) Increased intracellular Ca(2+) stimulates CaN, leading to the dephosphorylation and inactivation of inhibitor 1 and the activation of PP1. PP1 then dephosphorylates p-GluR1-Ser845 to elicit AMPA receptor (AMPAR) endocytosis and destabilization of the drug memory.
Insights
Drug memory destabilization involves N-methyl-d-aspartate receptors (NMDARs) and protein phosphatases. This research uncovers the cellular mechanisms that make drug memories vulnerable to disruption after reactivation.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Memory reconsolidation is a critical process for memory stabilization.
- Drug memories can become destabilized upon reactivation, offering a window for intervention.
- Understanding the cellular mechanisms of memory destabilization is crucial for developing treatments for addiction.
Purpose of the Study:
- To delineate the cellular mechanisms underlying the destabilization of drug-induced memories.
- To identify the specific molecular players involved in the destabilization process.
- To explore potential targets for disrupting drug memory reconsolidation.
Main Methods:
- Methamphetamine (MeAM) conditioned place preference (CPP) in mice to establish drug memory.
- Administration of anisomycin (ANI) post-retrieval to induce memory destabilization.
- Pharmacological manipulation using NMDAR antagonists (MK-801, ifenprodil, NVP-AAM077) and protein phosphatase inhibitors (cyclosporine A, FK-506, calyculin A, okadaic acid).
- Assessment of molecular changes including GluR1 phosphorylation, spine density, and AMPAR/NMDAR ratio in the basolateral amygdala (BLA).
Main Results:
- Memory destabilization was blocked by NR2B-containing NMDAR antagonists but not NR2A antagonists.
- MK-801 treatment reversed decreases in p-GluR1-Ser845, spine density, and AMPAR/NMDAR ratio in the BLA.
- Inhibition of protein phosphatases 2B (calcineurin) and 1 prevented ANI-induced destabilization.
- The findings indicate a pathway involving NR2B-NMDAR activation, calcium influx, calcineurin activation, PP1 activation, and subsequent dephosphorylation of p-GluR1-Ser845.
Conclusions:
- Memory destabilization is mediated by the activation of NR2B-containing NMDARs.
- This process leads to calcium influx, activating calcineurin and protein phosphatase 1.
- These phosphatases dephosphorylate GluR1, promoting AMPA receptor endocytosis and destabilizing drug memory.
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