Metabotropic Glutamate Receptor Signaling and Extinction Learning

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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.