Effects of Adenosine Signaling on Cocaine Reward and Relapse

药物成瘾是一种大脑疾病，对社会造成巨大损失，但尚未阐明有效的治疗方法。滥用药物的奖励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费和增加复发的易感性。本申请中研究的主要目标是增强我们对可卡因奖励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。长期或重复使用药物会导致大脑回路中的几种持久干扰，这些干扰会调节成瘾者的动机行为，促使成瘾者复发。脑桥核（NAc）是已知调节人类和啮齿动物中与成瘾相关的行为（即药物自我给药，复发和奖励）的大脑结构。在丘脑核内，多巴胺（D1和D2）和腺苷受体（A1和A2A）的亚型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是有趣的，因为它们：1）定位于NAc神经元的不同群体，2）对腺苷酸环化酶（介导细胞活性的细胞内酶）的活性起相互作用。目前尚不清楚这种细胞水平的相互活动如何转化为行为水平，特别是在成瘾的背景下。初步研究结果表明，腺苷A2A受体激动剂的全身给药的刺激减少可卡因寻求复发。因此，本申请的首要假设是，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。目的1将评估1）提高内源性腺苷水平和2）使用位置条件化范例直接刺激NAc腺苷A2A受体对可卡因奖赏的影响和使用渐进比率自我施用范例的可卡因强化。目的2将鉴定1）提高内源性腺苷水平和2）直接刺激NAc腺苷A2A受体对慢性可卡因自我施用后可卡因复发的影响。这些研究将为今后的工作提供基础，以确定与NAc内多巴胺和腺苷受体的相互作用相关的分子机制，有助于停止可卡因的使用。 公共卫生相关性：药物成瘾是一种严重的精神疾病，它涉及严重的动机障碍，导致行为控制的丧失，从而导致受折磨的个体及其周围的社交网络的破坏。这种疾病影响到数百万人，给社会造成巨大的社会和经济代价。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，并评估潜在治疗干预的主要生物靶点，以促进禁欲。

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.