Context-induced Cocaine Relapse: Influence of Cocaine Memory Reconsolidation

情境诱发的可卡因复吸：可卡因记忆再巩固的影响

• 批准号: 9403725
• 负责人: Rita A Fuchs Lokensgard
• 金额: $ 37.69万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9403725
• 关键词: 2-arachidonylglycerol; Amygdaloid structure; Anatomy; Behavior; Behavioral; Biochemical; Biological Assay; Brain region; Cells; Cocaine; Cocaine Dependence; Complex; Data; Desire for food; Development; Dorsal; Electrophysiology (science); Endocannabinoids; Environment; Exposure to; Extracellular Signal Regulated Kinases; Frequencies; Funding; Goals; Hippocampus (Brain); Immunohistochemistry; Kinetics; Lead; Learning; Link; Literature; Maps; Mediating; Mediator of activation protein; Memory; Mitogen-Activated Protein Kinases; Mono-S; Neighborhoods; Neuroanatomy; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Play; Procedures; Process; Protein Biosynthesis; Protocols documentation; Public Health; Pyramidal Cells; Relapse; Research; Research Project Grants; Retrieval; Role; Site; Stimulus; Synapses; Synaptic plasticity; Testing; Time; Update; Western Blotting; addiction; anandamide; base; cannabinoid receptor; cocaine exposure; cocaine relapse; craving; cue reactivity; disorder later incidence prevention; drug craving; drug maintenance; drug relapse; endocannabinoid signaling; endogenous cannabinoid system; fear memory; insight; locus ceruleus structure; long term memory; neural circuit; neuronal excitability; novel; optogenetics; programs; relating to nervous system; response; therapeutic target; therapy development

PROJECT SUMMARY/ABSTRACT Intractable cocaine craving precipitated by exposure to a cocaine-associated environmental context is a major factor contributing to drug relapse. This phenomenon depends on available long-term memories of context- response-drug associations. Recent findings indicate that associative memories become labile upon retrieval and need to undergo protein synthesis-dependent reconsolidation into long-term memory stores in order to be retained over time. Cocaine-induced pathology in memory reconsolidation may result in unusually salient or intrusive cocaine memories that manifest as increased cue reactivity and propensity for drug relapse in a drug- associated environment. Thus, the long-term goal of this research program is to enhance our understanding of the functional neuroanatomy and cellular mechanisms of cocaine memory reconsolidation. During the previous funding period, we have shown that protein synthesis-dependent memory reconsolidation occurs in the basolateral amygdala. Remarkably, this process is functionally dependent on neural activity in the dorsal hippocampus, even though the two brain regions do not share monosynaptic connections. Logically extending this line of research in this competitive renewal application, Specific Aim 1 will identify novel memory reconsolidation circuits. Based on our new preliminary findings, we will test the hypothesis that the locus coeruleus serves as a relay between the dorsal hippocampus and basolateral amygdala to permit cocaine memory reconsolidation. In addition, we will evaluate how the inhibition of specific pathways within this putative circuitry alters electrophysiological activity at the targeted terminal region of each pathway. During the previous funding period, we also identified cellular mechanisms that are necessary for cocaine memory reconsolidation. Systematically extending this line of research, Specific Aim 2 will identify novel cellular mechanisms of cocaine memory reconsolidation in the basolateral amygdala. Based on our preliminary findings, Aim 2 will focus on the endocannabinoids (eCB), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), in the basolateral amygdala. We will evaluate the extent to which memory reconsolidation is sufficient to produce changes in eCB levels, eCB degradation, and pyramidal cell excitability within the basolateral amygdala. In addition, we will test the hypothesis that AEA inhibits - whereas 2-AG facilitates – the reconsolidation of labile cocaine memories and the activation of a requisite cellular mediator of memory reconsolidation within the basolateral amygdala. To accomplish these Aims, we will utilize sophisticated behavioral, novel optogenetic functional disconnection, and electrophysiological recording protocols, as well as immunohistochemistry, quantitative Western blotting, and eCB biochemical assays. Overall, renewal of this productive research program has the potential to significantly advance our understanding of the neural basis of cocaine memory reconsolidation and to provide an essential conceptual framework for future research and addiction treatment development efforts.

项目总结/文摘