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Smoking underlies a major public health crisis worldwide, adversely impacting a person's health and placing a substantial and costly burden upon society. Tobacco use is implicated in approximately 480,000 deaths per year, making it the leading cause of preventable death in the United States. Despite a desperate need for treatment, current smoking cessation therapies are often ineffective. The addictiveness of nicotine drives the overall addiction to tobacco; therefore, it is of utmost importance to gain a better understanding of the neurobiological changes that underlie nicotine addiction. Drugs such as cocaine, alcohol and nicotine have different pharmacological effects, yet they all manipulate the experience of reward and motivation by interacting with a specific group of nerve cells in a brain region called the ventral tegmental area (VTA). These VTA cells produce the chemical messenger substance dopamine and are an integral part of the brain's reward circuitry. Research suggests that addiction is a result of drugs taking control of normal brain reward circuits that serve to reinforce behaviors related to survival (e.g., food, water and sex). While natural rewards activate the reward circuit until survival-related behaviors are learned, drugs of abuse continue to stimulate the circuit upon repeated exposures and induce fundamental and long-lasting maladaptive changes at synapses (i.e., connections) that influence the dopamine-producing nerve cells. In other words, nicotine and other drugs of abuse 'hijack' the brain's reward system. Recently, we discovered that a brain structure called the laterodorsal tegmentum (LDT) is a powerful modulator of VTA dopamine cell activity. The LDT is involved in reward-related behavior, nicotine increases cell activity in the LDT, and removal of the LDT ablates the rewarding effects of nicotine. However, in sharp contrast to our substantial knowledge of nicotine reward in dopamine cells in the VTA, relatively little is known about the involvement of the LDT in the development of nicotine addiction. This proposal describes a highly innovative pilot research project that aims to provide simultaneous anatomical, physiological, and behavioral evidence to elucidate the role of the LDT in the neurobiology of nicotine addiction. It is crucial to identify the precise mechanism of action of nicotine in the LDT in order to completely visualize the process by which nicotine manipulates the brain's natural reward system, the same process that underlies the establishment and maintenance of habitual tobacco smoking. To investigate nicotine reward in the LDT, we propose to employ a novel microendoscope imaging technology, which will allow us to peer into the brain of a freely moving mouse. We expect to be the first to visualize the activity of different types of LDT cells under normal conditions and in response to nicotine administration. Thus, we can determine with unprecedented detail nicotine's impact on different cell types in the LDT and identify LDT subpopulations that are particularly susceptible to nicotine exposure. Importantly, this understanding of the role of the LDT in nicotine addiction may serve as the foundation for development of targeted pharmaceutical treatments to combat nicotine addiction in the future, which is severely lacking in current medicine. |
