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Role of a6* nAChR-mediated signaling in nicotine withdrawal

Institution: SRI International
Investigator(s): Xiomara Perez, Ph.D.
Award Cycle: 2017 (Cycle 26) Grant #: 26IR-0023 Award: $579,971
Subject Area: Neuroscience of Nicotine Addiction and Treatment
Award Type: High Impact Research Project Award

Initial Award Abstract

Smoking is a leading cause of preventable deaths throughout the world as it leads to cancer, cardiovascular and pulmonary disease, and increased susceptibility to numerous other illnesses. Although these detrimental effects of tobacco use are probably not due to nicotine but to numerous irritants and/or carcinogens in smoke/tobacco, nicotine is a major psychoactive ingredient in tobacco that contributes to addiction and the smoking habit. Most smokers express a desire to quit. However, quitting smoking is often very challenging due to withdrawal symptoms that lead to frequent relapse. Clinical trials with nicotine replacement, bupropion or varenicline show that these treatments improve quit rates, with varenicline yielding the best results. However, the average success rate with varenicline is ~25%, and its use is associated with side effects such that its use must be discontinued. Thus, there is a pressing need to better understand the mechanisms related to nicotine addiction in order to develop improved therapeutic strategies. Smoking produces its pleasurable effects in the brain by acting at receptors that have a strong affinity for nicotine and are therefore called nicotinic receptors. There are multiple subtypes of nicotinic receptors in the brain that are linked to the maintenance of the smoking habit as well as the unpleasant symptoms that arise with smoking cessation. Of these, our work focuses on the role of a nicotinic receptor subtype known as alpha6beta2* receptors since these are exclusively localized to brain cells that produce dopamine, a chemical in the brain that is strongly involved in the rewarding effects of addictive drugs such as nicotine. Importantly, alpha6beta2* receptors are not expressed in the peripheral system. Thus, drugs targeting these receptors may have fewer side effects and consequently increase smoking cessation rates. Nicotine interacts with nicotinic receptors to control dopamine levels in the brain, with alpha6beta2* receptors playing a crucial regulatory role. The proposed work will investigate how selectively activating and inhibiting dopamine cells expressing alpha6beta2* receptors affect behavior during nicotine exposure and after its discontinuation. In addition, we will determine how the activity of these cells modulate dopamine signaling and the subsequent molecular changes that occur. To achieve this, we will use optogenetics and chemogenetics which are two novel tools that will enable us to selectively control dopamine cells expressing alpha6beta2* receptors within the brain reward pathway. Experiments will be performed in animals undergoing nicotine treatment as well as 1 d and 15 d after nicotine withdrawal. The results from this work will provide evidence of whether manipulating alpha6beta2* receptor-mediated dopamine signaling represents a good target for the development of smoking cessation drugs.