Effects of Adenosine Signaling on Cocaine Reward and Relapse

腺苷信号传导对可卡因奖赏和复吸的影响

基本信息

批准号：
8046960
负责人：
Ryan K Bachtell
金额：
$ 7.58万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-15 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8046960
关键词：
Abstinence Adenosine Adenosine A1 Receptor Adenosine A2A Receptor Adenylate Cyclase Affect Agonist Behavior Behavior Control Behavioral Biological Brain Brain Diseases Brain region Chronic Cocaine Complement Consumption Corpus striatum structure Cues Development Disease Dopamine Dopamine D2 Receptor Dopamine Receptor Drug Addiction Drug usage Enzymes Exposure to Foundations Future GTP-Binding Proteins Goals Human Individual Infusion procedures Injection of therapeutic agent Mediating Molecular Neurons Nucleus Accumbens Pharmaceutical Preparations Play Population Predisposition Property Psychological reinforcement Purinergic P1 Receptors Regulation Relapse Research Rewards Rodent Role Self Administration Signal Transduction Site Social Network Societies Stimulus Structure System Testing Therapeutic Intervention Time Translating Up-Regulation Work addiction cocaine use conditioning cost drug of abuse drug reinforcement drug relapse drug reward economic cost effective therapy inhibitor/antagonist mesolimbic system motivated behavior neurochemistry preference receptor severe mental illness social tool

项目摘要

DESCRIPTION (provided by applicant): Drug addiction is a brain disorder having enormous costs on society, yet effective treatments have not been elucidated. The rewarding properties of drugs of abuse contribute to initial drug taking behaviors that over time form an addiction that is characterized by increasing drug consumption and increasing susceptibility to relapse during periods of abstinence. The primary goal of the studies in this application is to enhance our understanding of the pharmacological mechanisms involved in cocaine reward and relapse that may aid in the development of more effective treatments. Chronic or repeated drug use results in several enduring perturbations in the brain circuitry that regulate motivated behavior prompting relapse in addicts. The nucleus accumbens (NAc) is a brain structure known to regulate behaviors associated with addiction (i.e. drug self-administration, relapse and reward) in both humans and rodents. Within the nucleus accumbens, subtypes of dopamine (D1 and D2) and adenosine receptors (A1 and A2A) modulate neuronal activity in a complementary, yet opposing manner. The interplay between these receptors and their subtypes is intriguing because they are: 1) localized to distinct populations of NAc neurons and 2) play reciprocal roles on the activity of adenylyl cyclase, an intracellular enzyme mediating cellular activity. It remains unclear how this reciprocal activity at the cellular level translates to the behavioral level, especially in the context of addiction. Preliminary findings demonstrate that stimulation of adenosine A2A receptors with systemic administration of A2A receptor agonists reduces relapse to cocaine seeking. Therefore, the overriding hypothesis for this application is that dopamine actions in the NAc that induce relapse will be tempered by increasing the reciprocal adenosine system in the NAc. Aim 1 will evaluate effects of 1) elevating endogenous adenosine levels and 2) directly stimulating NAc adenosine A2A receptors on the cocaine reward using a place-conditioning paradigm and cocaine reinforcement using a progressive-ratio self- administration paradigm. Aim 2 will identify the effects of 1) elevating endogenous adenosine levels and 2) directly stimulating NAc adenosine A2A receptors on cocaine relapse following chronic cocaine self- administration. Together these studies will provide a foundation for future work to identify the molecular mechanisms associated with the reciprocity of dopamine and adenosine receptors within NAc that contribute to cessation of cocaine use. PUBLIC HEALTH RELEVANCE: Drug addiction is a serious mental illness that involves significant motivational disturbances resulting in a loss of behavioral control leading to destruction of the afflicted individual as well as their surrounding social networks. This disease affects millions of people and generates enormous social and economic costs to society. The goal of this research is to better understand the disease as a whole, identify specific strategies to reduce cocaine use and evaluate major biological targets for potential therapeutic intervention to promote abstinence.

描述（由申请人提供）：吸毒成瘾是一种脑部疾病，给社会造成巨大损失，但有效的治疗方法尚未阐明。滥用药物的有益特性有助于最初的吸毒行为，随着时间的推移，形成成瘾，其特征是在戒断期间增加药物消耗和增加复发的可能性。本申请研究的主要目标是增强我们对可卡因奖赏和复发所涉及的药理学机制的理解，这可能有助于开发更有效的治疗方法。长期或反复吸毒会导致大脑回路产生一些持久的扰动，这些扰动会调节动机行为，从而促使成瘾者复吸。伏隔核 (NAc) 是一种大脑结构，已知可调节人类和啮齿动物与成瘾相关的行为（即药物自我给药、复发和奖励）。在伏隔核内，多巴胺亚型（D1 和 D2）和腺苷受体（A1 和 A2A）以互补但相反的方式调节神经元活动。这些受体及其亚型之间的相互作用很有趣，因为它们：1）定位于不同的 NAc 神经元群体，2）在腺苷酸环化酶（一种介导细胞活性的细胞内酶）的活性中发挥相互作用。目前尚不清楚细胞水平上的这种相互作用如何转化为行为水平，特别是在成瘾的情况下。初步研究结果表明，全身施用 A2A 受体激动剂刺激腺苷 A2A 受体可减少可卡因寻求的复发。因此，该应用的首要假设是，NAc 中诱导复发的多巴胺作用将通过增加 NAc 中的相互腺苷系统来缓和。目标 1 将评估 1) 提高内源性腺苷水平和 2) 使用位置调节范式直接刺激 NAc 腺苷 A2A 受体对可卡因奖励的影响，以及使用渐进比例自我给药范式评估可卡因强化的影响。目标 2 将确定 1) 提高内源性腺苷水平和 2) 直接刺激 NAc 腺苷 A2A 受体对长期自我服用可卡因后可卡因复发的影响。这些研究将为未来的工作奠定基础，以确定与 NAc 内多巴胺和腺苷受体相互作用相关的分子机制，从而有助于停止使用可卡因。公共卫生相关性：吸毒成瘾是一种严重的精神疾病，涉及严重的动机障碍，导致行为控制丧失，从而导致受折磨的个人及其周围的社交网络遭到破坏。这种疾病影响数百万人，给社会带来巨大的社会和经济成本。这项研究的目的是更好地了解整个疾病，确定减少可卡因使用的具体策略，并评估促进戒断的潜在治疗干预的主要生物靶点。