Effects of Adenosine Signaling on Cocaine Reward and Relapse

描述（由申请人提供）：吸毒成瘾是一种脑部疾病，对社会造成了巨大的代价，但有效的治疗方法尚未阐明。药物滥用的有益特性有助于最初的药物服用行为，随着时间的推移形成成瘾，其特征是药物消耗增加，并且在戒断期间增加复发的易感性。本应用研究的主要目的是增强我们对可卡因奖励和复发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。长期或反复使用毒品会导致大脑回路出现一些持久的紊乱，这些紊乱会调节促使成瘾者复发的动机行为。伏隔核（NAc）是一种已知的大脑结构，用于调节人类和啮齿动物与成瘾相关的行为（即药物自我管理，复发和奖励）。在伏隔核内，多巴胺亚型（D1和D2）和腺苷受体亚型（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是有趣的，因为它们是：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）的活性上发挥相互作用。目前还不清楚这种细胞水平上的相互作用是如何转化为行为水平的，尤其是在成瘾的情况下。初步研究结果表明，全身给予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，该应用的最重要的假设是，多巴胺在NAc中诱导复发的作用将通过增加NAc中的互惠腺苷系统而得到缓和。目的1将评估1)提高内源性腺苷水平和2)直接刺激NAc腺苷A2A受体对可卡因奖励的影响，使用场所条件反射范式和可卡因强化使用渐进比例自我给药范式。目的2将确定1)提高内源性腺苷水平和2)直接刺激NAc腺苷A2A受体对慢性可卡因自我给药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。

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.