Project Description:
Nicotine is the primary addictive constituent in tobacco. For an individual, chronic tobacco use is associated with a significant increase in heart disease and many forms of cancer; further, the health of non-tobacco users is negatively affected by second-hand smoke. With an estimated annual economic cost in the U.S around $167 billion, and millions of premature deaths, there are enormous potential benefits that would arise from a better understanding of nicotine dependence. To further add a layer of complexity, emerging studies have revealed important sex differences in nicotine addiction. Some studies suggest that women on average take less time than men to become dependent. Further, women make fewer attempts to quit smoking, remain abstinent for less time, have a higher relapse rate, and show less benefit from nicotine replacement therapy. If we are to have informed approaches to smoking cessation in men and women, more basic research is needed to identify the potential sources of these sex differences. Our goal in this application is to further advance this theory to elucidate behavioral and neural processes contributing to observed sex differences using a preclinical model of nicotine self-administration that we developed and refined in recent years. Employing a systems biology approach integrating behavioral, biochemical and computational aspects, the current proposal focuses to understand the changes occurring at the level of the synapsekey structures involved in neurotransmission and synaptic plasticity. Neurotransmission and the extensive sculpting and rewiring involved in synaptic plasticity regulate human learning, perception, emotion, thought, and many behaviors. Scientific inquiry into these synaptic changes holds great promise for providing insight into the biological basis of many neuropsychiatric disorders and psychopathologiesincluding addiction. Here, the emphasis is on chronic tobacco use and its associated nicotine dependence. To identify such synaptic signatures that could serve as sex-specific therapeutic targets for treating nicotine addiction, we propose the following two aims:
Aim 1: Examine potential sex difference in nicotine self-administration behavior across a range of nicotine doses.
Aim 2: Identification of differential sex-specific synaptic signatures in the striatum associated with chronic nicotine intake using quantitative mass spectrometry based proteomics.
There are two innovative aspects of this proposal. First, elucidating sex-specific neural correlates at the level of the synapse. Second, is the application of a powerful systems biology approach integrating three key modules: behavioral, biochemical and computational to glean novel insights and fill a significant gap in understanding the sex differences involving nicotine addiction. These identified leads could be directly tested in vitro or in vivo as potential targets to further our understanding on the mechanisms underlying these sex differences and will serve as a strong foundation for future studies and extramural grants.
Collaborator: Dr. Rick Bevins UNL
Dr. Babu Guda - UNMC (Consultant)
Unserved or Under-served Populations:
Racial or Ethnic Minorities, Disadvantaged Circumstances, Limited English, Geographic Areas
