Adenosine Receptor Involvement in Methamphetamine Reward and Relapse

腺苷受体参与甲基苯丙胺奖励和复发

基本信息

批准号：
8437847
负责人：
Ryan K Bachtell
金额：
$ 33.85万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8437847
关键词：
Abstinence Addictive Behavior Adenosine Adenosine A1 Receptor Adenosine Triphosphate Affect Agonist Area Behavior Behavior Control Behavioral Biological Brain Brain Diseases Brain region Cell physiology Cells Chronic Cocaine Complex Data Development Disease Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Dopamine Receptor Drug Addiction Drug usage Food GTP-Binding Proteins Goals Individual Intake Left Legal Ligands Mediating Medical Methamphetamine Methamphetamine dependence Modeling Neurobiology Neurons Nucleus Accumbens Output Pathway interactions Pharmaceutical Preparations Pharmacological Treatment Physiological Play Population Property Psychological reinforcement Public Health Purinergic P1 Receptors Rattus Receptor Signaling Regulation Relapse Research Rewards Role Schedule Self Administration Self-Administered Signal Transduction Social Network Societies Stimulus Synapses Therapeutic Intervention Training Treatment Efficacy addiction base conditioning design dopamine system drug relapse drug reward economic cost improved mesolimbic system methamphetamine abuse neural circuit neurochemistry novel postsynaptic preference presynaptic public health relevance receptor receptor expression research study severe mental illness sex social socioeconomics stimulant abuse treatment strategy vesicular monoamine transporter

Abstinence Addictive Behavior Adenosine Adenosine A1 Receptor Adenosine Triphosphate Affect Agonist Area Behavior Behavior Control Behavioral Biological Brain Brain Diseases Brain region Cell physiology Cells Chronic Cocaine Complex Data Development Disease Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Dopamine Receptor Drug Addiction Drug usage Food GTP-Binding Proteins Goals Individual Intake Left Legal Ligands Mediating Medical Methamphetamine Methamphetamine dependence Modeling Neurobiology Neurons Nucleus Accumbens Output Pathway interactions Pharmaceutical Preparations Pharmacological Treatment Physiological Play Population Property Psychological reinforcement Public Health Purinergic P1 Receptors Rattus Receptor Signaling Regulation Relapse Research Rewards Role Schedule Self Administration Self-Administered Signal Transduction Social Network Societies Stimulus Synapses Therapeutic Intervention Training Treatment Efficacy addiction base conditioning design dopamine system drug relapse drug reward economic cost improved mesolimbic system methamphetamine abuse neural circuit neurochemistry novel postsynaptic preference presynaptic public health relevance receptor receptor expression research study severe mental illness sex social socioeconomics stimulant abuse treatment strategy vesicular monoamine transporter

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项目摘要

DESCRIPTION (provided by applicant): Drug addiction is a brain disorder characterized by a progression toward compulsive drug use and relapse to drug seeking during abstinence. The primary goal of this new application is to enhance our understanding of the neurobiological and neurochemical mechanisms involved in methamphetamine abuse. The nucleus accumbens (NAc) is a brain region in a complex circuit that mediates initial drug reward and relapse during periods of abstinence. In the NAc, subtypes of dopamine (DA) and adenosine (ADO) receptors are co-localized in distinct subpopulations of neurons where they play antagonistic roles on cellular functioning. Thus, neurons having co-localization of either D1/A1 or D2/A2A receptor subtypes are known to form distinct output pathways, which influence specific aspects of behavior. The opposing actions of DA and ADO receptor subtypes can be mediated by direct physical interactions (i.e. heteromeric receptors), and/or through differential activation of G- protein mediated signaling cascades. How these opposing receptor subtypes localized to distinct neuronal populations regulate addictive behavior is unknown. We have evidence to suggest that stimulation of ADO A1, but not A2A, receptor subtype inhibits methamphetamine reinforcement and relapse. These effects differ from our findings that cocaine relapse is inhibited by non-selective stimulation of A1 and A2A receptors. Our overarching hypothesis is that chronic methamphetamine use specifically disrupts ADO A1 receptor signaling in the mesolimbic DA pathway, leaving DA D1 receptors unregulated contributing to methamphetamine reinforcement and relapse. In Aim 1, experiments will assess methamphetamine-induced changes on ADO receptor subtypes within the mesolimbic system. Additional studies will identify how methamphetamine intake alters the heteromeric interactions between ADO and DA receptor subtypes. Experiments in Aim 2 are designed to dissect the differential influence of specific ADO receptor subtypes on methamphetamine reward and reinforcement using place conditioning and progressive ratio responding, respectively. Aim 3 is designed to explore how ADO receptor subtypes may differentially influence reinstatement to methamphetamine seeking. Additional studies will explore how the differential influence of ADO receptor subtypes interact with methamphetamine seeking induced by specific DA receptor subtypes in the NAc. Together these studies offer the potential to better our understanding of the brain mechanisms involved in methamphetamine abuse that appear to be substantially different than mechanisms associated with another abused psychostimulant, cocaine. These studies offer the potential to create novel treatment strategies such as A1 receptor agonists or bivalent receptor ligands (e.g. D1 antagonist-A1 agonist) that could specifically target heteromeric receptors localized to specific subpopulations of neurons within specific neural circuits that undergo methamphetamine- induced alterations.

描述（由申请人提供）：药物成瘾是一种脑部疾病，其特征是在禁欲期间朝着强迫性药物使用和对药物寻求药物的复发。这种新应用的主要目标是增强我们对甲基苯丙胺滥用涉及的神经生物学和神经化学机制的理解。伏隔核（NAC）是复杂回路中的大脑区域，可在禁欲期间介导初始的药物奖励和复发。在NAC中，多巴胺（DA）和腺苷（ADO）受体的亚型共定位在神经元的不同亚群中，它们在细胞功能上起拮抗作用。因此，已知具有D1/A1或D2/A2A受体亚型共定位的神经元形成不同的输出途径，这会影响行为的特定方面。 DA和ADO受体亚型的相反作用可以通过直接的物理相互作用（即异源受体）和/或通过G-蛋白介导的信号级联反应来介导。这些对立受体亚型如何定位于不同神经元种群调节成瘾行为。我们有证据表明，刺激ADO A1而不是A2a，受体亚型抑制甲基苯丙胺的增强和复发。这些作用与我们的发现不同，认为可卡因复发受到A1和A2A受体的非选择性刺激的抑制。我们的总体假设是，慢性甲基苯丙胺的使用特异性破坏了中脑脱脂的DA途径中ADO A1受体信号传导，而DA D1受体则不受管制，从而有助于甲基苯丙胺增强和复发。在AIM 1中，实验将评估甲基苯丙胺诱导的中溶胶系统中ADO受体亚型的变化。其他研究将确定甲基苯丙胺摄入如何改变ADO和DA受体亚型之间的异源相互作用。 AIM 2中的实验旨在剖析特定ADO受体亚型对甲基苯丙胺奖励的差异影响，并分别使用位置调节和渐进率响应进行甲基苯丙胺奖励和增强。 AIM 3旨在探索ADO受体亚型如何差异地影响恢复到甲基苯丙胺寻求。其他研究将探讨ADO受体亚型的差异影响如何与NAC中特定DA受体亚型诱导的甲基苯丙胺相互作用。这些研究共同提供了我们对甲基苯丙胺滥用涉及的大脑机制的理解，这些机制似乎与与另一种滥用心理刺激剂可卡因相关的机制大不相同。这些研究提供了创建新型治疗策略的潜力，例如A1受体激动剂或二价受体配体（例如D1拮抗剂A1激动剂），这些抗体可能针对特定神经元内神经元的异源型受体的特定神经元的特定神经回路群体，这些受体受到甲基苯丙胺诱导的改变。