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会与正常学习和记忆过程的神经机制相互作用。为了支持这一点，最近有研究表明，消除恐惧和药物条件行为是由N-甲基-D-天冬氨酸（NMDA）受体部分激动剂D-环丝氨酸。增强NMDA受体功能的另一种方法是通过刺激与NMDA受体活性正偶联的5型代谢型谷氨酸受体（mGluR 5）。最近，已经开发了几种mGluR 5正变构调节剂，包括全身活性化合物3-氰基-N-（1，3-二苯基-1H-吡唑-5-基）苯甲酰胺（CDPPB）。此类化合物目前处于临床前开发中，用于治疗以NMDA受体功能减退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促进可卡因寻求行为的大鼠静脉内可卡因自我管理以及以下的地方条件反射的灭绝。我们的总体假设（将在以下特定目标下进行测试）是，通过正变构调节剂增强mGluR 5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。在具体目标1中，我们将进一步表征CDPPB促进大鼠可卡因寻求行为消退的能力。在这一目标中，我们将进行剂量反应分析的能力CDPPB，以提高收购和巩固的消退学习静脉内可卡因自我管理。还将评估CDPPB对可卡因寻求行为消退作用的潜在性别差异和药理学选择性。具体目标2将确定是否增强消退学习诱导的mGluR 5正变构调节剂CDPPB推广到其他环境背景。这将通过检查在消退训练期间给予的CDPPB对大鼠可卡因寻求行为随后的背景恢复的影响来评估。最后，在具体目标3中，我们将确定涉及mGluR 5正变构调节剂促进可卡因寻求行为消退的能力的神经回路。在这一目标中，我们建议研究的mGluR 5积极变构调节剂对可卡因寻求行为的灭绝后，网站特定的显微注射到几个与可卡因相关的区域的大鼠大脑，包括基底外侧杏仁核，背海马，腹内侧前额叶皮层，核丘脑核心，和背外侧尾壳核。总之，拟议的研究将提供一个药理学和解剖学的基础上使用mGluR 5积极变构调节剂在增强收购和巩固的消退学习后，药物自我管理的大鼠，这将有望导致更好地了解消退学习的神经基板和改进的治疗药物成瘾的治疗方法在人类。本申请的目的是为mGluR 5功能的正变构调节剂的潜在用途提供临床前基础，以促进可卡因成瘾背景下的消退学习。如果这些化合物最终被证明在增强人类的灭绝学习方面是有效的，这将代表药物成瘾治疗的重大公共卫生进步，并将显著降低成瘾对社会的医疗、社会经济和法律的成本。这些化合物也可能用于焦虑症（如创伤后应激障碍）的消退治疗。

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.