title: Involvement of protein phosphatases in the destabilization of methamphetamine-associated contextual memory.
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.
authors.affiliation: Institute of Basic Medical Sciences and Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan 701.
authors.forename: Yang-Jung
authors.initials: YJ
authors.lastname: Yu
authors.affiliation: Institute of Basic Medical Sciences and Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan 701.
authors.forename: Chien-Hsuan
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Institute of Basic Medical Sciences and Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan 701.
authors.forename: Chih-Hua
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Institute of Basic Medical Sciences and Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan 701 powu@mail.ncku.edu.tw.
authors.forename: Po-Wu
authors.initials: PW
authors.lastname: Gean
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000201:enzymology*; D000818:Animals; D000841:Anisomycin / Q000008:administration & dosage; D020013:Calcium Signaling / Q000187:drug effects; D003214:Conditioning, Classical; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology; D016291:Dizocilpine Maleate / Q000008:administration & dosage; D008297:Male; D000069077:Memory Consolidation / Q000187:drug effects / Q000502:physiology*; D011939:Mental Recall / Q000187:drug effects / Q000502:physiology; D008694:Methamphetamine / Q000008:administration & dosage*; D008810:Mice, Inbred C57BL; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage; D011810:Quinoxalines / Q000008:administration & dosage; D018091:Receptors, AMPA / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: C498554:5-(alpha-methyl-4-bromobenzylamino)phosphonomethyl-1,4-dihydroquinoxaline-2,3-dione; C121001:NR2B NMDA receptor; D011500:Protein Synthesis Inhibitors; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D008694:Methamphetamine; D000841:Anisomycin; D016291:Dizocilpine Maleate; D010749:Phosphoprotein Phosphatases