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：
8995196
负责人：
Ryan K Bachtell
金额：
$ 37.28万
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/8995196
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 Health 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 cocaine relapse conditioning design dopamine system drug relapse drug reward economic cost improved mesolimbic system methamphetamine abuse methamphetamine use neural circuit neurochemistry novel postsynaptic preference presynaptic receptor receptor expression research study severe mental illness sex social socioeconomics stimulant abuse treatment strategy vesicular monoamine transporter vesicular release

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，其特征是发展成强迫性药物使用并在戒断期间复发寻求药物。这一新应用的主要目标是增强我们对甲基苯丙胺滥用所涉及的神经生物学和神经化学机制的理解。伏隔核（NAc）是复杂回路中的一个大脑区域，介导最初的药物奖励和戒断期间的复发。在 NAc 中，多巴胺 (DA) 和腺苷 (ADO) 受体的亚型共定位于不同的神经元亚群中，在细胞功能中发挥拮抗作用。因此，已知具有 D1/A1 或 D2/A2A 受体亚型共定位的神经元会形成不同的输出途径，从而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物理相互作用（即异聚受体）和/或通过G蛋白介导的信号级联的差异激活来介导。这些定位于不同神经元群的相反受体亚型如何调节成瘾行为尚不清楚。我们有证据表明，刺激 ADO A1 受体亚型（而非 A2A）可以抑制甲基苯丙胺强化和复发。这些效应与我们的发现不同，我们的发现是可卡因复发受到 A1 和 A2A 受体非选择性刺激的抑制。我们的总体假设是，长期使用甲基苯丙胺会特异性破坏中脑边缘 DA 通路中的 ADO A1 受体信号传导，使 DA D1 受体不受调节，从而导致甲基苯丙胺强化和复发。在目标 1 中，实验将评估甲基苯丙胺诱导的中脑边缘系统内 ADO 受体亚型的变化。其他研究将确定甲基苯丙胺的摄入如何改变 ADO 和 DA 受体亚型之间的异聚相互作用。目标 2 中的实验旨在分别使用位置调节和渐进比例响应来剖析特定 ADO 受体亚型对甲基苯丙胺奖赏和强化的差异影响。目标 3 旨在探索 ADO 受体亚型如何对恢复甲基苯丙胺寻求产生不同的影响。其他研究将探讨 ADO 受体亚型的不同影响如何与 NAc 中特定 DA 受体亚型诱导的甲基苯丙胺寻求相互作用。这些研究共同为我们提供了更好地理解甲基苯丙胺滥用所涉及的大脑机制的潜力，这些机制似乎与另一种滥用的精神兴奋剂可卡因相关的机制有很大不同。这些研究提供了创造新的治疗策略的潜力，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），可以特异性靶向位于经历甲基苯丙胺诱导改变的特定神经回路内特定神经元亚群的异聚受体。