Metabotropic Glutamate Receptor Signaling and Extinction Learning

描述（由申请人提供）：目前的证据表明，灭绝是一种新的和积极的学习形式。因此，促进灭绝的尝试最终将与正常学习和记忆过程背后的神经机制相互作用。为了支持这一点，最近有研究表明，n -甲基- d -天冬氨酸（NMDA）受体部分激动剂d -环丝氨酸促进了恐惧和药物条件行为的消除。另一种增强NMDA受体功能的方法是通过刺激5型代谢性谷氨酸受体（mGluR5），该受体与NMDA受体活性正偶联。近年来，已开发出几种mGluR5阳性变构调节剂，包括系统活性化合物3-氰- n -（1,3-二苯基- 1h -吡唑-5-基）苯酰胺（CDPPB）。这些化合物目前正处于临床前开发阶段，用于治疗以NMDA受体功能低下为特征的精神分裂症。我们已经产生了新的和令人鼓舞的初步数据，表明CDPPB促进大鼠在静脉注射可卡因自我给药和场所条件反射后的可卡因寻求行为的消失。我们的总体假设将在以下具体目标下进行验证，即通过正变构调节剂增强mGluR5功能可能为增强药物成瘾背景下的消退学习提供一种新的治疗方法。在Specific Aim 1中，我们将进一步描述CDPPB促进大鼠可卡因寻求行为消失的能力。为此，我们将对CDPPB在静脉注射可卡因自我给药后增强消退学习的获得和巩固的能力进行剂量反应分析。还将评估CDPPB在消除可卡因寻求行为方面的潜在性别差异和药理学选择性。特异性目的2将确定mGluR5阳性变构调节剂CDPPB诱导的消退学习增强是否可推广到其他环境背景。这将通过检查在灭绝训练期间给予CDPPB对大鼠可卡因寻求行为随后情境恢复的影响来评估。最后，在Specific Aim 3中，我们将确定涉及mGluR5阳性变构调节剂促进可卡因寻求行为消失能力的神经回路。在这一目的中，我们建议研究mGluR5阳性变构调剂在大鼠大脑中几个与消失相关的区域（包括基底外侧杏仁核、背侧海马、腹内侧前额叶皮层、伏隔核和背外侧尾状壳核）进行特异性微注射后，对可卡因寻找行为消失的影响。综上所述，本研究将为mGluR5阳性变构调节剂在大鼠自我给药后增强消退学习的习得和巩固提供药理学和解剖学基础，这将有助于更好地了解消退学习的神经基质，并改进人类药物成瘾的治疗方法。该应用的目的是为mGluR5功能的正变构调节剂在可卡因成瘾背景下促进消退学习的潜在应用提供临床前基础。如果这类化合物最终被证明能有效地增强人类的戒毒学习能力，这将是在治疗吸毒成瘾方面取得的一项重大公共卫生进展，并将大大减少吸毒成瘾对社会造成的医疗、社会经济和法律成本。这些化合物也可能用于治疗创伤后应激障碍等焦虑症。

DESCRIPTION (provided by applicant): Current evidence suggests that extinction is a form of new and active learning. Thus, attempts at facilitating extinction will ultimately interact with the neural mechanisms underlying normal learning and memory processes. In support of this, it has recently been shown that extinction of fear- and drug-conditioned behaviors is facilitated by the N-methyl-D-aspartate (NMDA) receptor partial agonist D-cycloserine. An alternative approach to enhancing NMDA receptor function is via stimulation of type 5 metabotropic glutamate receptors (mGluR5), which are positively coupled to NMDA receptor activity. Recently, several mGluR5 positive allosteric modulators have been developed, including the systemically active compound 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB). Such compounds are currently in preclinical development for the treatment of schizophrenia, which is characterized by NMDA receptor hypofunction. We have generated novel and encouraging Preliminary Data showing that CDPPB facilitates the extinction of cocaine-seeking behavior in rats following intravenous cocaine self-administration as well as following place conditioning. Our overall hypothesis, which will be tested under the following Specific Aims, is that enhancement of mGluR5 function by positive allosteric modulators may provide a novel therapeutic approach for enhancing extinction learning in the context of drug addiction. In Specific Aim 1, we will further characterize the ability of CDPPB to facilitate extinction of cocaine-seeking behavior in rats. In this aim, we will conduct a dose-response analysis of the ability of CDPPB to enhance both the acquisition and consolidation of extinction learning following intravenous cocaine self-administration. Potential gender differences and the pharmacological selectivity of the effects of CDPPB on extinction of cocaine-seeking behavior will also be assessed. Specific Aim 2 will determine whether enhancement of extinction learning induced by the mGluR5 positive allosteric modulator CDPPB generalizes to other environmental contexts. This will be assessed by examining the effects of CDPPB administered during extinction training on subsequent contextual reinstatement of cocaine-seeking behavior in rats. Finally, in Specific Aim 3, we will determine the neural circuitry involved the ability of mGluR5 positive allosteric modulators to facilitate extinction of cocaine-seeking behavior. In this aim, we propose to examine the effects of an mGluR5 positive allosteric modulator on extinction of cocaine-seeking behavior following site-specific microinjections into several extinction-related regions of the rat brain, including the basolateral amygdala, dorsal hippocampus, ventromedial prefrontal cortex, nucleus accumbens core, and dorsolateral caudate-putamen. Together, the proposed studies will provide a pharmacological and anatomical basis for the use of mGluR5 positive allosteric modulators in enhancing the acquisition and consolidation of extinction learning following drug self-administration in rats, which will hopefully lead to a better understanding of the neural substrates of extinction learning and improved therapies for the treatment of drug addiction in humans. The goal of this application is to provide a preclinical basis for the potential use of positive allosteric modulators of mGluR5 function to facilitate extinction learning in the context of cocaine addiction. Should such compounds eventually prove to be effective in enhancing extinction learning in humans, this would represent a major public health advancement in the treatment of drug addiction, and would significantly reduce the medical, socioeconomic and legal costs of addiction to society. Such compounds could also be of potential use in extinction therapy of anxiety disorders such as post-traumatic stress disorder.