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Role of mGluR7 in nicotine dependence

Institution: University of California, San Diego
Investigator(s): Xia Li, Ph.D.
Award Cycle: 2011 (Cycle 20) Grant #: 20KT-0046 Award: $270,000
Subject Area: Nicotine Dependence
Award Type: New Investigator Awards

Initial Award Abstract
Tobacco smoking is a severe public health problem that exacts a high toll both in terms of societal costs and personal suffering. However, the neural mechanisms underlying nicotine dependence, the major factor driving chronic tobacco smoking, are not fully understood. A better understanding of the neurobiology of nicotine dependence is crucial for developing more effective treatments for this devastating disorder. Glutamate is the major excitatory neurotransmitter in the brain and plays a critical role in drug abuse including tobacco smoking. Scientific research indicates that the rewarding, motivational and reward-enhancing effects of nicotine, and relapse to tobacco smoking after a period of abstinence are related to increases in glutamate transmission in the brain. Based on this recognition, several current medication development strategies have focused on new treatment that decrease glutamate transmission and therefore ameliorate nicotine dependence. The effects of glutamate are mediated by activation of two types of glutamate receptors in the brain, ionotropic glutamate receptors (iGluR) and metabotropic glutamate receptors (mGluRs). Although direct blockade of iGluR and mGluR has shown some efficacy in the treatment of different aspects of nicotine dependence, such compounds may produce serious unwanted side effects in humans. Alternatively, efforts have been undertaken to inhibit glutamate transmission with compounds that have modulatory action on mGluRs and, therefore, may lack unwanted side-effects. mGluR7, represent a novel target for manipulation of the glutamate system to treat nicotine dependence. However, the role of mGluR7 in nicotine addiction has been largely unexplored due to the lack of selective pharmacological tools. Recently, scientists developed AMN082, a selective mGluR7 allosteric agonist (i.e., a molecule that binds to a different binding site than glutamate on mGluR7, where it potentiates the effectiveness of glutamate at mGluR7). We found that activation of mGluR7 by AMN082 decreased glutamate release, inhibited the reinforcing and reward enhancing effects of cocaine and heroin, as well as attenuated cocaine- or heroin-induced reinstatement of drug-seeking behavior. However, AMN082 did not produce aversive effects or disruption of normal behaviors. These observations suggest that mGluR7 may be a novel promising target in medication development for the treatment of drug addiction with no unwanted side effects. The proposed studies will determine whether activation of mGluR7 has potential for the treatment of nicotine dependence. We hypothesize that an mGluR7 allosteric agonist will block nicotine effects relevant to nicotine dependence, including the positive rewarding, motivational, and reward-enhancing effects of nicotine, as well as reinstatement of nicotine seeking after a period of abstinence, a model of relapse to nicotine consumption. We predict that the mGluR7 allosteric agonist AMN082 will inhibit these nicotine-related behaviors, suggesting that mGluR7 allosteric agonists may be effective for the treatment of nicotine dependence. Further, we will determine neurochemical/neurobiological mechanisms mediating the effects of AMN082 by administering AMN082 in specific brain areas involved in the rewarding effects of nicotine and using the selective mGluR7 antagonist. The proposed work will increase our understanding of glutamate mechanisms in nicotine reward and dependence. Such improved insight into the neurobiology of nicotine dependence is necessary to develop interventions that can break the causal chain in nicotine addiction, one of TRDRP’s Research Priorities. Moreover, the proposed work will assess the potential of a novel medication target for the treatment of nicotine dependence, mGluR7. Interventions directed at this novel target may lead to more effective treatments for nicotine addiction and smoking cessation, another of TRDRP’s Research Priorities. By highlighting novel, promising targets for the treatment of tobacco smoking, the proposed work will contribute significantly to an important research effort aimed at improving public health.

Metabotropic glutamate 7 (mGlu7) receptor: A target for medication development for the treatment of cocaine dependence
Periodical: Neuropharmacology Index Medicus:
Authors: Xia Li, Zheng-Xiong Xi ZX, Athian Markou ART
Yr: 2012 Vol: Nbr: Abs: Pg: