Adenosine Receptor Involvement in Methamphetamine Reward and Relapse

描述(申请人提供)：药物成瘾是一种脑部疾病，其特征是在戒毒期间逐渐发展为强迫性药物使用和反复寻求药物。这一新应用的主要目标是加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)是大脑复杂环路中的一个区域，在戒酒期间调节最初的药物奖励和复发。在NAC中，多巴胺(DA)和腺苷(ADO)受体的亚型共同分布在不同的神经元亚群中，它们在细胞功能上发挥拮抗作用。因此，已知具有D1/A1或D2/A2A受体亚型共定位的神经元形成不同的输出通路，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的物理相互作用(即异构体受体)和/或通过G蛋白介导的信号级联的不同激活来介导。这些相互对立的受体亚型定位于不同的神经元群体，如何调控成瘾行为尚不清楚。我们有证据表明，刺激ADO A1受体亚型，而不是A2A受体亚型，可以抑制甲基苯丙胺的强化和复发。这些效应不同于我们的发现，即通过对A1和A2A受体的非选择性刺激来抑制可卡因复发。我们的主要假设是，慢性甲基苯丙胺的使用特异性地扰乱了中脑边缘DA通路中的ADO A1受体信号，使DA D1受体处于无调控状态，从而导致甲基苯丙胺的强化和复发。在目标1中，实验将评估甲基苯丙胺对中脑边缘系统内ADO受体亚型的影响。其他研究将确定甲基苯丙胺摄入量如何改变ADO和DA受体亚型之间的异构体相互作用。目的2的实验分别利用位置条件反射和递进比率反应来分析特定的ADO受体亚型对甲基苯丙胺奖赏和强化的不同影响。目的3旨在探索ADO受体亚型如何不同地影响对甲基苯丙胺寻求的恢复。其他研究将探索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找相互作用。总之，这些研究为我们更好地了解甲基苯丙胺滥用所涉及的大脑机制提供了可能性，这些机制似乎与另一种滥用的精神刺激剂可卡因有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可能性，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)，它们可以特异性地靶向异构体受体，这些异构体受体定位于经历甲基苯丙胺诱导的改变的特定神经回路中的特定神经元亚群。

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.