Adenosine Receptor Involvement in Methamphetamine Reward and Relapse

描述（申请人提供）：药物成瘾是一种大脑疾病，其特征是在戒断期间向强迫性药物使用和复发寻求药物的方向发展。这项新应用的主要目标是提高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。脑桥核（NAc）是一个复杂回路中的大脑区域，介导最初的药物奖励和戒断期间的复发。在NAc中，多巴胺（DA）和腺苷（ADO）受体的亚型共定位于不同的神经元亚群中，在那里它们对细胞功能起拮抗作用。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，其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物理相互作用（即异聚体受体）和/或通过G蛋白介导的信号传导级联的差异活化来介导。这些定位于不同神经元群体的相反受体亚型如何调节成瘾行为尚不清楚。我们有证据表明，ADO A1，而不是A2A，受体亚型的刺激抑制甲基苯丙胺加固和复发。这些影响不同于我们的研究结果，即可卡因复吸被A1和A2A受体的非选择性刺激抑制。我们的总体假设是，慢性甲基苯丙胺的使用，特别是破坏ADO A1受体信号在中脑边缘DA通路，使DA D1受体不受管制的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诱导的中脑边缘系统内ADO受体亚型的变化。进一步的研究将确定甲基苯丙胺的摄入如何改变ADO和DA受体亚型之间的异聚体相互作用。目的2中的实验被设计为分别使用位置条件反射和累进比率反应来剖析特定ADO受体亚型对甲基苯丙胺奖赏和强化的差异影响。目的3是为了探讨ADO受体亚型如何可能差异影响恢复甲基苯丙胺寻求。其他研究将探讨ADO受体亚型的差异影响如何与NAc中特定DA受体亚型诱导的甲基苯丙胺寻求相互作用。总之，这些研究提供了更好地了解甲基苯丙胺滥用所涉及的大脑机制的可能性，这些机制似乎与另一种滥用精神兴奋剂可卡因的机制有很大不同。这些研究提供了创造新的治疗策略的潜力，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），其可以特异性靶向位于经历甲基苯丙胺诱导的改变的特定神经回路内的特定神经元亚群的异聚体受体。

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.