Molecular Cognition of Addiction

成瘾的分子认知

基本信息

批准号：
7880589
负责人：
STEPHAN G ANAGNOSTARAS
金额：
$ 29.98万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7880589
关键词：
Abstinence Accidents Acquired Immunodeficiency Syndrome Affect Amygdaloid structure Behavior Behavioral Behavioral Paradigm Brain Calcium Calcium/calmodulin-dependent protein kinase Calmodulin Cessation of life Chronic Cocaine Cognition Corpus striatum structure Crime Cues Dependence Development Drug Addiction Drug Metabolic Detoxication Drug effect disorder Drug usage Drug user Exposure to Genetic Goals Health Hippocampus (Brain)Homelessness Imprisonment Injection of therapeutic agent Learning Lesion Light Liver diseases Malignant Neoplasms Measures Mediating Medical Memory Modeling Molecular Molecular Biology Mus Neurobiology Neurons Pathway interactions Pharmaceutical Preparations Phosphotransferases Plague Poverty Process Productivity Property Prosencephalon Psychological reinforcement Recruitment Activity Relapse Role Self Administration Short-Term Memory Specificity Staging Structure Synaptic plasticity System Time Translations Violence Withdrawal addiction behavioral sensitization calmodulin-dependent protein kinase II cost craving drug of abuse drug reinforcement effective therapy genetic manipulation memory acquisition neuroadaptation preference relating to nervous system response social

项目摘要

DESCRIPTION (provided by applicant): Both memory and addiction produce long-lasting changes in behavior and result in chronic neural adaptations in response to repeated neural activity. It is therefore likely that memory and addiction recruit some of the same molecular mechanisms of synaptic plasticity in the same neural structures. In the present proposal, we explore the parallels between addiction and memory by examining the impact of genetic and anatomical manipulations known to affect memory on addiction-related behavioral plasticity. In a simple behavioral paradigm in mice we can rapidly quantify psychomotor sensitization to repeated cocaine injections, as well as the conditioned response to cues associated with cocaine administration, the contextual control over the expression of cocaine sensitization, and conditioned place preference induced by cocaine. First, we use this paradigm to evaluate the role of the hippocampus and amygdala in addiction-related memory. Second, we use inducible and region-specific disruption of calcium/calmodulin- dependent protein kinase II (CaMKII), a criticial kinase in memory formation, in addiction. Finally, we examine the role of calcium calmodulin in addiction. A benefit of using modern genetic manipulation is the ability to better localize key neuroadaptations through disruption of dendritic translation, and inducible region-specific disruption of alpha-CaMKI in the forebrain and striatum. The inducible and reversible molecular manipulations we propose, post-induction disruption of CaMKII or calcium calmodulin, actually have the potential to reverse sensitization to cocaine and related memories. Taken together, these studies will evaluate the parallels between memory and addiction-related behavioral plasticity and shed considerable light on whether manipulations of memory will prove useful in the treatment of addiction.Project Narrative Addiction is a major social and medical problem affecting millions of compulsive drug users. In the present proposal we examine the relationship between memory and addiction at the level of the brain. If memory and addiction prove to be highly related, disruptions of memory may prove highly useful in the treatment of addiction.

描述（由申请人提供）：记忆和成瘾都会产生持久的行为变化，并导致针对重复的神经活动的慢性神经适应。因此，记忆和成瘾很可能在相同的神经结构中招募了一些相同的突触可塑性分子机制。在本提案中，我们通过检查已知影响记忆的遗传和解剖操作对成瘾相关行为可塑性的影响，探索成瘾和记忆之间的相似之处。在小鼠的简单行为范式中，我们可以快速量化对重复可卡因注射的精神运动敏化，以及对与可卡因给药相关的线索的条件反应、对可卡因敏化表达的上下文控制以及可卡因诱导的条件位置偏好。首先，我们使用这个范式来评估海马体和杏仁核在成瘾相关记忆中的作用。其次，我们在成瘾中使用钙/钙调蛋白依赖性蛋白激酶 II (CaMKII) 的诱导性和区域特异性破坏，CaMKII 是记忆形成的关键激酶。最后，我们研究了钙调蛋白在成瘾中的作用。使用现代基因操作的一个好处是能够通过破坏树突翻译以及前脑和纹状体中 α-CaMKI 的诱导区域特异性破坏来更好地定位关键神经适应。我们提出的诱导和可逆分子操作，即诱导后破坏 CaMKII 或钙调蛋白，实际上有可能逆转对可卡因和相关记忆的敏感性。总而言之，这些研究将评估记忆与成瘾相关行为可塑性之间的相似之处，并为记忆操纵是否有助于治疗成瘾提供重要线索。项目叙事成瘾是影响数百万成瘾药物的主要社会和医学问题用户。在本提案中，我们在大脑层面研究记忆与成瘾之间的关系。如果记忆和成瘾被证明是高度相关的，那么破坏记忆可能对治疗成瘾非常有用。