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：
8239507
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/8239507
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 Health 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 public health relevance 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）：吸毒是一种脑部疾病，在社会上成本巨大，但尚未阐明有效的治疗方法。滥用药物的奖励性能有助于最初的药物服用行为，随着时间的流逝，成瘾的特征是在禁欲期间增加药物消耗和增加对复发的敏感性。在本应用中，研究的主要目的是增强我们对可卡因奖励和复发涉及的药理机制的理解，这可能有助于开发更有效的治疗方法。长期或重复的药物使用会导致大脑回路中的几种持久扰动，这些扰动调节动机行为促使成瘾者复发。伏隔核（NAC）是一种大脑结构，该结构已知，它调节了与人类和啮齿动物的成瘾相关的行为（即药物自我给药，复发和奖励）。在伏隔核中，多巴胺（D1和D2）的亚型和腺苷受体（A1和A2A）以互补但相反的方式调节神经元活性。这些受体与它们的亚型之间的相互作用很有趣，因为它们是：1）局部在NAC神经元的不同种群中，2）在腺苷酸环化酶的活性（一种介导细胞活性的细胞内酶）上扮演相互作用。目前尚不清楚细胞级别的这种相互活性如何转化为行为水平，尤其是在成瘾的背景下。初步发现表明，用A2A受体激动剂全身给药的腺苷A2A受体刺激减少了寻求可卡因的复发。因此，该应用的重大假设是，NAC中的多巴胺作用将通过增加NAC中的相互腺苷系统来诱发复发。 AIM 1将评估1）使用位置调节范式和可卡因增强型，使用渐进ratio ratio自我给药范式来评估可卡因奖励的NAC腺苷A2A受体对可卡因奖励的升高的影响。 AIM 2将确定1）升高内源性腺苷水平的影响，以及2）直接刺激NAC腺苷A2A受体对慢性可卡因自我给药后可卡因复发的影响。这些研究将共同为将来的工作提供基础，以确定NAC中多巴胺和腺苷受体互惠性相关的分子机制，这有助于停止可卡因的使用。公共卫生相关性：吸毒是一种严重的精神疾病，涉及重大的动机障碍，导致行为控制丧失，从而破坏受苦的人及其周围的社交网络。这种疾病会影响数百万的人，并为社会产生巨大的社会和经济成本。这项研究的目的是更好地理解整个疾病，确定减少可卡因使用的特定策略，并评估主要的生物学靶标，以促进潜在的治疗干预措施以促进禁欲。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Initial d2 dopamine receptor sensitivity predicts cocaine sensitivity and reward in rats.

DOI：
10.1371/journal.pone.0078258
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Merritt KE;Bachtell RK
通讯作者：
Bachtell RK

Stimulation of adenosine receptors in the nucleus accumbens reverses the expression of cocaine sensitization and cross-sensitization to dopamine D2 receptors in rats.

DOI：
10.1016/j.neuropharm.2012.06.038
发表时间：
2012-11
期刊：
Neuropharmacology
影响因子：
4.7
作者：
Hobson BD;Merritt KE;Bachtell RK
通讯作者：
Bachtell RK

Effects of adolescent caffeine consumption on cocaine sensitivity.

青少年咖啡因摄入量对可卡因敏感性的影响。

DOI：
10.1038/npp.2014.278
发表时间：
2015
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
0
作者：
O'Neill,CaseyE;Levis,SophiaC;Schreiner,DrewC;Amat,Jose;Maier,StevenF;Bachtell,RyanK
通讯作者：
Bachtell,RyanK

Persistent reduction of cocaine seeking by pharmacological manipulation of adenosine A1 and A 2A receptors during extinction training in rats.