Behavioral effects of methamphetamine & imidazoline I2 receptor ligands

描述(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疾病，它招募了多个大脑区域和神经递质系统。尽管进行了几十年的研究，但还没有开发出有效的药物疗法来治疗MA成瘾。咪唑啉I2受体可能成为药物成瘾药物治疗的新靶点。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，行为学研究表明，内源性咪唑啉受体配体胍丁胺可以减弱阿片类药物的成瘾相关效应。然而，药理学上选择性的I2受体配体是否调节滥用药物的成瘾相关效应，我们知之甚少。我们最近观察到选择性I2受体激动剂2-BFI显著减弱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受体是治疗MA成瘾的新药物靶点的概念验证。在令人兴奋的初步数据的指导下，这一假设将通过追求两个具体目标来检验：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)使用药物识别程序(目标2)在区分MA或I2受体激动剂2-BFI的动物中检查I2受体配体和MA之间的相互作用。综上所述，这些研究系统地评估了I2受体配体对MA成瘾相关(如奖赏和区别刺激)效应的影响。这些数据将为I2受体激动剂治疗MA成瘾和相关兴奋剂的潜在治疗价值提供有价值的信息。此外，在拟议的研究中获得的数据可能有助于进一步确定新的基于I2受体的药物治疗MA成瘾的方法。

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.