Glutamate and Craving for Cocaine

谷氨酸和对可卡因的渴望

基本信息

批准号：
7600512
负责人：
Peter W Kalivas
金额：
$ 23.74万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-02-10 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7600512
关键词：
6-Cyano-7-nitroquinoxaline-2,3-dione Abbreviations Abstinence Acids Actins Adenylate Cyclase Aminobutyric Acids Animal Model Behavioral Binding Brain Cell Membrane Permeability Chimeric Proteins Chronic Cocaine Cystine Dependovirus Dopamine Dopamine Receptor Drug Addiction Drug Combinations Drug Exposure Enkephalins F-Actin Functional disorder Globus Pallidus Glutamate Receptor Glutamates Goals Green Fluorescent Proteins Homer 3 Injection of therapeutic agent Intervention Long-Term Potentiation Measures Mediator of activation protein Metabotropic Glutamate Receptors Microdialysis Microinjections Modeling Molecular Target Mutate N-Methylaspartate Nucleus Accumbens Opioid Pharmaceutical Preparations Phosphotransferases Prefrontal Cortex Proteins Rattus Reagent Regulation Relapse Research Personnel Role Self-Administered Series Signal Transduction Stress Surface Testing Training Ventral Tegmental Area Virus Withdrawal addiction connective tissue-activating peptide craving density gamma-Aminobutyric Acid human RASD1 protein metabotropic glutamate receptor 2 mu opioid receptors neuroimaging novel postsynaptic presynaptic prevent programs protein expression receptor research study transmission process

项目摘要

DESCRIPTION (provided by applicant): Among the most insidious features of drug addiction is the propensity to relapse after periods of prolonged abstinence. The enduring vulnerability to relapse reflects long-term cellular changes in brain circuitry. Experiments in animal models of drug-seeking reveal adaptations in the series circuit consisting of the glutamatergic projection from the prefrontal cortex (RFC) to the nucleus accumbens and the GABA/enkephalin projection from the accumbens core (NAcore) to the ventral pallidum (VP). Identifying these projections as potentially critical in animal models of addiction has led to a search for enduring cellular changes in the PFC, NAcore and VP that underlie drug-seeking. This proposal will use a reinstatement model in rats trained to self-administer cocaine to characterize adaptations in this circuit that underlie drug-seeking. It is hypothesized that the PFC - NAcore - VP projection is a series circuit that undergoes pathological changes in protein expression and function as a result of repeated drug exposure and withdrawal. To test the veracity of this hypothesis candidate proteins will be manipulated in order to reduce cocaine- or stress-induced reinstatement of drug-seeking. In aim #1 the role of dopamine receptor subtypes in the PFC in regulating reinstatement will be examined by a combination of drug microinjection and microdialysis. In aims #2 and #3 the role of pre- and postsynaptic proteins that regulate glutamate transmission in the NAcore will be examined, including the cystine-glutamate exchanger, mGluR2/3, Homer and actin. A combination of microdialysis and injection of reagents to manipulate protein levels such as virus and Tat fusion proteins will be used. Finally, in the VP the role of mu opioid regulation of GABA release in drug-seeking will be characterized. The overarching goal of the proposal is to identify novel molecular targets for pharmacotherapeutic intervention in cocaine craving and relapse.

描述（由申请人提供）：吸毒成瘾最阴险的特征之一是长期戒毒后容易复发。持久的复发脆弱性反映了大脑回路的长期细胞变化。药物寻求动物模型实验揭示了串联回路的适应性，该串联回路由从前额叶皮层（RFC）到伏隔核的谷氨酸能投射和从伏隔核（NAcore）到腹侧苍白球（VP）的 GABA/脑啡肽投射组成。确定这些预测在成瘾动物模型中具有潜在的关键作用，促使人们寻找导致药物寻求的 PFC、NAcore 和 VP 中持久的细胞变化。该提案将使用经过训练的老鼠的恢复模型来自我注射可卡因，以表征这一回路中导致药物寻求的适应性。据推测，PFC - NAcore - VP 投影是一个串联电路，由于重复的药物暴露和停药而导致蛋白质表达和功能发生病理变化。为了测试这一假设的准确性，将对候选蛋白质进行操纵，以减少可卡因或压力引起的药物寻求恢复。在目标#1中，将通过药物显微注射和微透析相结合来检查PFC中多巴胺受体亚型在调节恢复中的作用。在目标 #2 和 #3 中，将检查调节 NAcore 中谷氨酸传输的突触前和突触后蛋白的作用，包括胱氨酸-谷氨酸交换器、mGluR2/3、Homer 和肌动蛋白。将使用微透析和注射试剂的组合来控制蛋白质水平，例如病毒和 Tat 融合蛋白。最后，在 VP 中，将描述 mu 阿片类药物对 GABA 释放的调节在药物寻求中的作用。该提案的总体目标是确定药物治疗干预可卡因渴望和复发的新分子靶点。