Caveolins, Striatal Toxicity and Methamphetamine Addiction

小窝蛋白、纹状体毒性和甲基苯丙胺成瘾

基本信息

批准号：
9348473
负责人：
Chitra D Mandyam
金额：
--
依托单位：
VA SAN DIEGO HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9348473
关键词：
Adaptive Behaviors Address Age Animal Model Animals Behavior Behavioral Belief Brain Caring Caveolins Characteristics Cholesterol Chronic Corpus striatum structure Dopamine D1 Receptor Dorsal Drug Addiction Event Extracellular Signal Regulated Kinases Genetic Genetic Techniques Goals Hyperactive behavior Impairment Intake Knowledge Lead MAPK3 gene Mediating Membrane Lipids Membrane Microdomains Methamphetamine Methamphetamine dependence Mitogen-Activated Protein Kinases Modeling Molecular Motivation Neurobiology Neurons Pathology Pattern Pharmacology Phenotype Play Pre-Clinical Model Publishing Rattus Receptor Signaling Reinforcement Schedule Relapse Reporting Research Rewards Rodent Model Role Saline Scaffolding Protein Self Administration Self-Administered Signal Transduction Sphingolipids Subfamily lentivirinae Sucrose Techniques Testing Therapeutic Intervention Toxic effect Veterans Work addiction behavioral response caveolin 1 cholesterol-binding protein clinically relevant drug seeking behavior experience functional disability methamphetamine effect overexpression prevent protein expression receptor expression repaired substance abuse treatment

项目摘要

Summary Dopamine D1 receptors (D1Rs) in the dorsal striatum are hypothesized to play a major role in methamphetamine (Meth) addiction, and self-administration paradigms of Meth intake (clinically relevant models of Meth addiction) have reported that Meth self-administration increases D1R expression in the striatum and systemic D1R blockade decreases responding to Meth and reduces Meth seeking. Systemic D1 receptor antagonism in Meth experienced animals also prevented some aspects of maladaptive alterations; e.g. Meth-induced hyperphosphorylation of ERK1/2 in the striatum and Meth reward, indicating that enhancement of ERK1/2 by Meth is an intracellular signal transduction mechanism contributing to the maladaptive plasticity associated with reinforcing effects of Meth. These studies suggest that progressive increases in the intake of Meth over extended access schedules of reinforcement may lead to persistent neurobiological alterations in the striatum through aberrant increases in D1R expression and ERK1/2 activity. Therefore, the proposal will determine whether D1Rs and ERK1/2 activity in the dorsal striatum plays a role in establishing compulsive-like self-administration in animals experiencing Meth over extended access schedules of reinforcement. New evidence demonstrates that D1R signaling occurs in discrete plasmalemmal microdomains termed membrane/lipid rafts. Lipid rafts are enriched in cholesterol- and sphingolipid and the cholesterol binding and scaffolding protein caveolin-1 (Cav-1). Cav-1 is important in regulating D1R signaling, turnover and function. Therefore, we also seek to determine whether Cav-1 in D1R expressing neurons plays a role in mediating the maladaptive behavioral responses in compulsive Meth taking and seeking in Meth addicted animals. We will test these hypotheses using well-established rodent models of compulsive-like Meth self-administration and state-of-the-art genetic and pharmacological techniques to determine the role of D1Rs, ERK1/2 activity and Cav-1 in Meth addiction. Understanding the cellular and molecular mechanisms underlying Meth addiction in the dorsal striatum in animal models that demonstrate compulsive-like behavior has tremendous potential for identifying therapeutic interventions for reducing Meth addiction and maladaptive patterns of Meth seeking.