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Effect of mGlu7 receptor manipulation on actions of nicotine

Institution: University of California, San Diego
Investigator(s): Astrid Stoker, Ph.D.
Award Cycle: 2012 (Cycle 21) Grant #: 21FT-0022 Award: $89,777
Subject Area: Disparities /Prevention/ Cessation/ Nicotine Dependence
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract

The development of novel smoking cessation medications is essential to halt the devastating effects of tobacco smoking on global health, because currently available smoking cessation medications remain largely ineffective in the majority of people that attempt to quit smoking. Tobacco smoking is, at least partly, maintained by dependence on nicotine. Therefore, an improved understanding of the mechanisms underlying the effects of nicotine on the brain is crucial for the development of novel smoking cessation medications. Glutamate, a substance found in the brain, is the major excitatory neurotransmitter, that is “messenger”, in the brain and plays an important role in several aspects of nicotine dependence, including the rewarding and motivational effects of nicotine and relapse to tobacco smoking after a quit attempt. Glutamate binds to sites on brain cells that are called glutamate receptors. These glutamate receptors are widely dispersed throughout the reward pathways of the brain. Several drugs that decrease glutamate levels in brain reward pathways show effectiveness in decreasing the effects of nicotine that are associated with nicotine dependence. Metabotropic glutamate 7 (mGlu7) receptors, one subtype of glutamate receptors, have recently become of interest as novel targets for the treatment of dependence on various drugs of abuse, such as alcohol and cocaine. However, little is known about the involvement of this receptor in nicotine dependence. The study of the involvement of mGlu7 receptors in drug dependence was long delayed by the lack of selective pharmacological drugs for these receptors, until the recent synthesis of AMN082, a compound that activates the mGlu7 receptor and MMPIP, a compound that blocks the actions of the mGlu7 receptor. Scientists recently demonstrated that activation of mGlu7 receptors decreases the rewarding effects of cocaine, and most importantly preliminary data from our laboratory demonstrated similar results for nicotine self-administration. The involvement of mGlu7 receptors in the effects of nicotine is further supported by the presence of mGlu7 receptors in the ventral tegmental area (VTA), a brain region of importance in the rewarding and motivational effects of nicotine. We propose to study the effects of activation and blockade of the mGlu7 receptor in the VTA on nicotine-taking and nicotine-seeking behaviors. We expect that activation of mGlu7 receptors with AMN082 and genetic overexpression of mGlu7 receptors in the VTA will reduce nicotine taking and relapse to nicotine seeking after a period of abstinence. In addition, we expect that blockade of mGlu7 receptors with MMPIP and genetic knockdown of mGlu7 receptors in the VTA may have opposite effects, and potentiate nicotine taking and nicotine seeking. The detailed characterization of the role of mGlu7 receptors in nicotine taking and nicotine seeking will inform us about the involvement of this receptor in nicotine dependence, and is likely to lead to the identification of a novel target in the continued global effort to find efficacious treatments to assist people to quit the harmful tobacco smoking habit, thereby addressing Research Priority 2 of TRDRP, “to advance innovative research in nicotine addiction”.