Behavioral effects of methamphetamine & imidazoline I2 receptor ligands

描述（由申请人提供）：甲基苯丙胺（MA）和相关兴奋剂滥用仍然是全球主要的公共卫生问题。MA成瘾是一种高度复杂的神经病理性疾病，涉及多个脑区和神经递质系统。尽管进行了数十年的研究，但尚未开发出治疗MA成瘾的有效药物疗法。咪唑啉I2受体可能成为药物成瘾治疗的新靶点。越来越多的证据表明，I2受体激动剂可以调节多巴胺能系统和行为研究表明，内源性咪唑啉受体配体胍丁胺的阿片类药物的成瘾相关的影响的衰减。然而，鲜为人知的是，选择性I2受体配体是否调节成瘾相关的药物滥用的影响。我们最近观察到一种选择性的I2受体激动剂2-BFI能明显减弱MA诱导的行为敏感化和条件性位置偏爱。本申请的目的是评估I2受体是用于治疗MA成瘾的新型药物靶标的概念验证。在令人兴奋的初步数据的指导下，这一假设将通过两个具体的目标进行验证：1）检查I2受体激动剂2-BFI和拮抗剂tracizoline对MA诱导的条件性位置偏爱的发展和恢复的影响（目标1）; 2）在动物中检测I2受体配体和MA之间的相互作用，使用药物辨别程序辨别MA或I2受体激动剂2-BFI（目的2）。总的来说，所提出的研究系统地评估了I2受体配体对成瘾相关的（例如，奖励和歧视刺激）的影响。这些数据将提供有关I2受体激动剂用于治疗MA和相关兴奋剂成瘾的潜在治疗价值的有价值的信息。此外，在拟议的研究中获得的数据可能有助于确定进一步的新的I2受体为基础的药物治疗成瘾MA。

DESCRIPTION (provided by applicant): Methamphetamine (MA) and related stimulant abuse remains a major public health concern globally. MA addiction is a highly complicated neuropathological disorder that recruits multiple brain regions and neurotransmitter systems. Despite decades of research, no effective pharmacotherapy has yet been developed for treating MA addiction. Imidazoline I2 receptors may represent a novel target for developing pharmacotherapy of drug addiction. Accumulating evidence indicates that I2 receptor agonists can modulate the dopaminergic system and behavioral studies have demonstrated the attenuation of the addiction-related effects of opioids by the endogenous imidazoline receptor ligand agmatine. However, little is known of whether pharmacologically selective I2 receptor ligands modulate the addiction-related effects of drugs of abuse. We recently observed that a selective I2 receptor agonist, 2-BFI, markedly attenuates MA induced behavioral sensitization and conditioned place preference. The objective of the present application is to evaluate the proof-of-concept that the I2 receptor is a novel drug target for the treatment of MA addiction. Guided by exciting preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) examine the effect of an I2 receptor agonist, 2-BFI, and an antagonist, tracizoline, on the development and reinstatement of MA-induced conditioned place preference (Aim 1); 2) examine the interaction between I2 receptor ligands and MA in animals discriminating MA or the I2 receptor agonist, 2-BFI, using a drug discrimination procedure (Aim 2). Collectively, the proposed studies systematically evaluate the effects of I2 receptor ligands on the addiction- related (e.g., rewarding and discriminative stimulus) effects of MA. These data will provide valuable information regarding the potential therapeutic value of I2 receptor agonists for the treatment of addiction to MA and related stimulants. In addition, data obtained in the proposed investigation may contribute to the identification of further novel I2 receptor based pharmacotherapies for addiction to MA.