of the Parent Grant: Role of cotinine in nicotine use disorders 5R01DA044242-02 (PI: Ding) The major objective of the current project is to understand the reward-related actions of cotinine (COT), the major metabolite of nicotine (NIC), and its potential role in the development of NIC use disorder. The long- term goal is to provide a better understanding of COT-related mechanisms in NIC reinforcement and provide rationale for research targeting the actions of COT for future development of new therapies for aiding smoking cessation. The overarching hypothesis is that COT plays an important role in the development of NIC abuse and addiction through a combination of mechanisms, including its own reinforcing and craving-/relapse-like effects, unique mechanisms involved in these effects, its interactions with NIC to promote reinforcing and craving-/relapse-like effects. A multidisciplinary approach encompassing behavioral neuroscience and neurochemistry will be employed in this project. Thus, Aim 1 will determine the reward-related behavioral and neurochemical effects of COT as compared to NIC.
Aim2 will determine potential similarities or differences in mechanisms involved in the reinforcing effects of COT vs NIC.
Aim 3 will examine potential interactions between COT and NIC in promote reinforcement.
And Aim 4 will investigate the craving-/relapse-like properties of COT and its interactions with NIC to promote craving-/relapse-like effects using reinstatement models. Potential sex differences in COT?s actions will also be examined. This is a highly novel project. Information attained will not only significantly increase our understanding of COT-related mechanisms underlying NIC reinforcement and the development of NIC use disorders, but also highlight the importance of targeting COT as a new strategy for treating NIC use disorders. ROLE OF COTININE IN NICOTINE USE DISORDERS: ALZHEIMER?S SUPPLEMENT (Response to NOT- AG-18-008 Alzheimer?s Disease and its related Dementias (AD/ADRD)-focused Administrative supplements for NIH grants that are not focused on Alzheimer?s disease) Tobacco smoking is an addictive disease with devastating consequences. Alzheimer?s disease (AD) is a degenerative brain disease and the most common cause of dementia. Epidemiological analyses have revealed complex association between smoking and AD. However, mechanisms underlying their association have not been understudied. The parent grant indicates that nicotine (NIC) and its major metabolite, cotinine (COT), produce reinforcing effects and are major factors maintaining continuous smoking. Therefore, the objective of this project is to investigate association between the reinforcing effects of NIC/COT and their effects on AD-related behavioral and brain pathological changes. AD is characterized by progressive cognitive impairment, brain amyloid-?-peptide (A?) deposition resulted from aberrant cleavage of A? precursor protein (APP), and tau hyper-phosphorylation (p-tau). The central hypothesis is that NIC/COT will produce more robust reinforcing effects in AD rats than control rats, which will be associated with cognition-enhancing effects and their effects on reducing A? formation and p-tau.
Aim 1 will examine the reinforcing effects of NIC/COT, their effects on cognitive function, and on APP processing and tau phosphorylation in wild-type F344 and TgF344- AD rats. Intravenous self-administration and radial arm maze will be used to determine reinforcing effects and cognitive function, respectively. Enzymes (e.g., ?-secretases and BACE1), and proteins/peptides (e.g., sAPP?, sAPP?, A?, tau, p-tau) involved in AD brain pathology will be determined with Western blot and ELISA.
Aim 2 will develop primary human fetal brain (HFB) cultures to examine the effects of NIC/COT on APP processing and tau phosphorylation. In addition, the nicotinic receptor antagonist mecamylamine will be used to probe mechanisms underlying these effects. A long-time collaborator and renowned scientist will bring in expertise in HFB culturing and protein assays, in addition to more than two decades of experience in AD research. The NIH-funded Model-AD center within IU Stark Neuroscience Research Institute (SNRI) will provide TgF344-AD rats. The synergistic approach and complementary expertise of key investigators, along with excellent resource at SNRI, constitute the major strength of this proposal. This highly significant project is deeply rooted in the parent grant with the examination of the reinforcing effects of NIC/COT and the use of mecamylamine for probing potential different mechanisms underlying NIC/COT?s effects. It is also a logic expansion from the parent grant to examine the effects of NIC/COT on AD pathology given complex association between smoking and AD. A multidisciplinary approach encompassing behavioral and molecular techniques is employed to provide converging evidence to elucidate mechanisms underlying NIC/COT use and AD pathogenesis. The studies with NIC/COT at physiological concentrations and cultured primary HFB will have high translational value. In addition, this project has far-reaching impact on public health with evidence of complex association between smoking and AD development, thus forming basis for future public health policy.

Public Health Relevance

The project will provide critical insights into the important role of cotinine in the development of nicotine abuse and addiction. The unique reinforcing and craving-/relapse-like effects of cotinine and its interaction with nicotine will be studied. Results will significantly increase our understanding the cotinine-related mechanisms in the development of nicotine use disorders, and will shed light on developing new pharmacotherapies targeting cotinine for aiding smoking cessation.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Berton, Olivier Roland
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Indiana University-Purdue University at Indianapolis
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United States
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