Glutamatergic Mechanisms Underlying Nicotine Addiction and Relapse Following Nicotine Reduction

This is an R03 proposal to examine whether reductions in nicotine levels in tobacco products will impact relapse in a preclinical model of nicotine reinforcement. This will be examined using behavioral economic and neurophysiological measures, and results will provide support for a larger R01 study that will more thoroughly examine this topic with a focus on informing tobacco regulatory science. Tobacco use is one of the leading preventable causes of death1. Nicotine is acknowledged as being the main substance responsible for maintaining smoking behavior2, and its reinforcing properties have been demonstrated across species3-5 using the intravenous self-administration paradigm. A variety of strategies have been employed to reduce tobacco use, including nicotine replacement6, 7, pharmacotherapies8, and the reduction of nicotine quantity in tobacco products9. For decades, reduction of nicotine content in cigarettes has been postulated as an effective way to prevent tobacco product abuse in new tobacco users, and to increase smoking cessation in established smokers10-13. In 2009, federal regulation of nicotine content was established by the Family Smoking Prevention and Tobacco Control Act in the United States to reduce addiction to cigarette smoking11. Specifically, reduction of nicotine content in tobacco products is a control strategy intended to decrease smoking dependence that reduces nicotine content over time (although not to zero)14, resulting in gradual reduction of intake and dependence12, 13, 15. Evidence suggests many users may increase their smoking when provided with low nicotine cigarettes, and the increased smoking may confer greater risk than smoking fewer cigarettes with higher nicotine levels16. Several preclinical and human clinical trials have been done to characterize the contribution of reduced nicotine products to smoking cessation efforts16, 17, however no studies to date have examined the role of nicotine reduction in relapse vulnerability. Here we propose to determine if nicotine reduction leads to a decrease in relapse vulnerability and its associated neurobiological sequelae. We are the appropriate team to investigate this question because we have expertise in preclinical models of nicotine self-administration and the examination of underlying neurophysiological changes, and because we have developed a unique behavioral economic (BE) model that measures the elasticity of nicotine demand and motivation in a manner that can be generalized across species. These techniques will be integrated for this study, which will be both rigorous and innovative. We will utilize a daily within-session nicotine BE protocol with conditioned cues associated with different doses of nicotine. The model efficiently characterizes individual differences in response to nicotine reduction, and utilizes the same variables measured in daily (between-session) BE models that have been shown in numerous species to predict subsequent relapse behavior18, 19. Using this model, we will examine whether nicotine reduction inhibits cue-triggered nicotine seeking and rapid, transient glutamatergic synaptic plasticity (t-SP) in medium spiny neurons within the nucleus accumbens core (NAcore). A principle hypothesis of the proposed studies is that glutamatergic prefrontal cortex-NAcore projections induce pathological changes in glutamate levels contributing to relapse of nicotine-seeking behavior. We recently reported that NAcore t-SP occurs during initiation of cue-induced nicotine seeking20, 21, and correlates with magnitude of reinstatement. Thus, NAcore t-SP may have important value as a nicotine relapse-associated neural biomarker. This proposal will provide preliminary information regarding nicotine reduction as a relapse prevention strategy, including potential underlying mechanisms, and will support development of an R01 to more thoroughly examine whether gradual or abrupt nicotine reduction changes features of nicotine dependence and relapse vulnerability in animals previously exposed to normal (i.e., higher) doses of nicotine.