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The development of novel smoking cessation medications is essential to halt the devastating effects of tobacco smoking on global health. The major impediment to successful smoking cessation is the discouragingly high rate of relapse after a period of abstinence, due to the addictive nature of nicotine contained in cigarettes. For example, nicotine facilitates the formation of strong associations between environmental stimuli and nicotine taking. Thus, specific stimuli associated with smoking can generate strong urges to smoke, and elicit nicotine seeking and relapse to smoking. In addition, there are negative affective symptoms associated with nicotine withdrawal, including depression and anxiety. These symptoms also contribute to persisting nicotine use and drive relapse to smoking after abstinence because the individual attempts to alleviate these symptoms by smoking. Research indicates that glutamate, a major excitatory substance found in the brain, plays an important role in nicotine dependence. Long-term smoking induces long-lasting changes affecting the function of the glutamate system, which may underlie the negative affective symptoms of nicotine withdrawal and how the strong associations between environmental stimuli and smoking drive the individual to continue the harmful tobacco smoking habit. Thus, we hypothesize that modulating the function of the glutamate system may help alleviate the nicotine withdrawal symptoms and promote extinction of the associations between nicotine taking and environment stimuli, and therefore, prevent relapse to smoking. To test this hypothesis, the present studies will modulate glutamate transmission by targeting one subtype of glutamate receptors, named metabotropic glutamate receptor (mGluR) 7, and explore the potential efficacy of mGluR7 manipulations on preventing relapse to nicotine taking. Specifically, we will explore whether modulation of this specific type of glutamate receptor can alleviate the negative affective signs of nicotine withdrawal and promote extinction of nicotine-cue associations. Results from the proposed studies will provide detailed characterization of the role of mGluR7 in the forces that drive the persistence of nicotine taking and relapse to tobacco smoking even after a period of abstinence. This research 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.
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