The Role of Alpha2 nAChR Subtypes in Nicotine Withdrawal
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Tobacco dependence is known to kill nearly half a million people each year in the United States alone. Given this staggering statistic, it is surprising that people continue to smoke cigarettes. While most smokers would like to quit, only a small percentage of them are successful. Continued tobacco use after a quit attempt (or relapse) is attributed to the negative response the human body has to the sudden elimination of tobacco use. This negative response is known as a withdrawal syndrome. The syndrome is characterized in people as having trouble sleeping, irritability, anxiety, impatience and an increased desire for more cigarettes (i.e. craving). By determining ways of decreasing the withdrawal syndrome in humans, we could help individuals stop smoking and increase life expectancy.Research has demonstrated that the withdrawal syndrome is caused by the continued exposure to a chemical in cigarettes called nicotine. Nicotine is known to bind to certain proteins in the brain, called nicotinic receptors, to ultimately influence how they function. One function of nicotinic receptors is their ability to release molecules in the brain, like dopamine, that are associated with the feeling of pleasure (i.e. reward). Over time, nicotine exposure leads to persistent changes in the function of nicotinic receptors to modify the pleasurable effects of nicotine in the brain. The consequence leads to increased nicotine intake, in part, due to modified rewarding effects of nicotine, thereby ultimately enhancing the harmful consequences of tobacco consumption.Over the last 30 years, to better understand the mechanisms involved in nicotine dependence, our laboratory has helped discover the majority of the nicotinic receptors, showed where they are found in the brain and demonstrated their functional role in brain cells. Furthermore, members of our group established that nicotinic receptors are remarkably complex. They are made up of five separate subunit proteins, named alpha and beta. Multiple alpha and beta proteins are present in the brain and their dynamic interactions lead to diverse nicotinic receptor assemblies. One of the long-term goals of our laboratory has been to identify which alpha and beta proteins interact to form functional nicotinic receptor assemblies in the brain. Such information would help drug designers know the best protein target in the brain for the development of better smoking cessation medications. The information is important, as the available medications to date, while helpful, do not lead to long-term quit rates in the human smoker.Recently, our laboratory engineered strains of laboratory mice deficient in certain nicotinic receptor subunits (i.e. alpha2 deficient mice). Using these animals, data illustrates that mice lacking individual alpha or beta subunits do not have symptoms that resemble tobacco withdrawal in humans, thus suggesting a therapeutic target for smoking cessation medications. However, the functional makeup of the nicotinic receptor assemblies mediating withdrawal remains unknown. Thus, the aim of our current proposal is to use molecular and genetic techniques to identify the exact subunit composition of the nicotinic receptors found in selective brain regions involved in the reduction of nicotine withdrawal symptoms. In so doing, we hope to better understand the mechanisms leading to tobacco dependence, which would aid in the development of selective therapeutic targets for the treatment of tobacco withdrawal. This is of critical significance as smoking cessation is the only known measure to prevent the long-term health consequences of cigarette smoking.