Mechanisms Regulating Cocaine Memory Strength

调节可卡因记忆强度的机制

• 批准号: 9408065
• 负责人: Mary M Torregrossa
• 金额: $ 10.11万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9408065
• 关键词: Address; Amygdaloid structure; Behavior; Behavioral; Behavioral Mechanisms; Calcineurin; Calmodulin; Chemosensitization; Clinical; Cocaine; Cues; Data; Electrophysiology (science); Equilibrium; Event; Extinction (Psychology); Female; Goals; Homosynaptic Depression; Individual; Learning; Maintenance; Measures; Mediating; Memory; Methods; Modeling; Molecular; Neuronal Plasticity; Pathway interactions; Pattern; Pharmaceutical Preparations; Phosphopeptides; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphoserine; Phosphotransferases; Physiological; Process; Protein Analysis; Protein Dephosphorylation; Proteomics; Rattus; Regulation; Relapse; Reporting; Research; Research Personnel; Role; Self-Administered; Serine; Sex Characteristics; Signal Pathway; Signal Transduction; Societies; Synapses; Testing; Time; Tissues; Training; Viral; addiction; base; calcineurin phosphatase; calmodulin-dependent protein kinase II; cohort; conditioned fear; craving; cue reactivity; disorder later incidence prevention; drug of abuse; effective therapy; experimental study; fear memory; follow-up; improved; male; memory process; mimetics; mutant; non-drug; novel; phosphoproteomics; pre-clinical; prevent; therapy development

Project Summary/Abstract Addictive disorders are a huge burden on both the individual and on society. Unfortunately, there are few effective treatments, partially due to the persistence of drug-associated memories that drive craving and relapse. Therefore, recent research has focused on finding ways to reduce the strength of drug-associated memories to prevent relapse. Memory strength can be reduced by either disrupting the association between a cue and a drug via extinction or by inhibiting the reconsolidation of the memory after a reminder event. Both strategies have been effective in preclinical and clinical models, but in some cases, a memory meant to be weakened, is instead strengthened due to unintentional enhancement of reconsolidation or inhibition of extinction. In order to address this problem, we have analyzed changes in protein phosphorylation after a memory undergoes extinction vs. reconsolidation to identify signaling cascades that are selective to either memory process, or that ideally regulate the two processes in opposite directions. Identification of opposing signaling events could allow the development of treatments that both enhance extinction and inhibit reconsolidation, reducing the strength of the drug-associated memories that drive relapse. Our preliminary data strongly suggest that opposing Ca2+-related signaling events in the basolateral amygdala (BLA) mediate the reconsolidation vs. extinction of a memory associated with self-administered cocaine. We will expand our identification of opposing signaling events in Aim 1 of the proposed studies, including increasing the number of proteins analyzed, expansion of the time course of analysis, and extending the analysis to females. Moreover, we will follow-up on the exciting findings from our initial study, which include 1) identification of a novel phosphorylation event on Ca2+ -calmodulin-dependent kinase 2 alpha (CaMKIIα, phospho-serine 331) induced by extinction and reduced during reconsolidation that functions to inhibit kinase activity, and 2) a general decrease in protein phosphorylation after extinction, implicating activation of a phosphatase, such as calcineurin. Our data led us to hypothesize that extinction training, in addition to involving new learning mechanisms, can also oppose normal reconsolidation processes. We propose that this occurs within the same circuits via Ca2+-regulated synaptic depotentiation mechanisms. Extinction-induced synaptic depotentiation and differences in CaMKII and calcineurin signaling have been reported for conditioned fear memories, but have not been examined for cocaine-associated memories. Thus, using a combination of approaches in Aims 2 & 3, we will determine if CaMKIIα inhibition via S331 phosphorylation, and activation of calcineurin phosphatase, can reduce cocaine memory strength to decrease cue-induced reinstatement via enhancement of extinction AND inhibition of reconsolidation. We will also determine if these signaling pathways directly regulate each other and synaptic strength in the same or different pathways. Determination of the mechanisms regulating cocaine memories will lead to novel targets for relapse prevention treatment development.

项目总结/文摘