This application is in response to NIH/PSH 2010-2 'Omnibus solicitation for SBIR/STTR Grant Application'under NIDA 2, "Development of Alternate Drug Delivery Dosage Forms for Drugs Abuse Studies". Through the use of tobacco, nicotine is one of the most heavily used addictive drugs and the leading preventable cause of disease, disability, and death in the U.S. To understand the numerous effects of nicotine on the brain and body, and to develop more effective and safer medications for smoking cessation and for treatment of tobacco- related diseases, nicotine dependent animal models are required. Currently available nicotine application methods for in vivo animal models have a number of limitations. Nicotine fails to reach the gas-exchange region in the lungs (the alveoli);therefore, the time course and magnitude of the rise in arterial nicotine levels are not comparable to those of humans when smoking cigarettes. The goal of this grant is to develop a non-invasive method and toolkit for delivering nicotine to rodent models that ensure an adequate and controllable amount entering circulation and the brain at the same rate nicotine enters the bodies of humans smoking cigarettes. Aim 1. To develop a novel nicotine delivery method for rodents and to validate it with animal testing. We will demonstrate the effectiveness of nicotine delivery by determining median lethal concentration (LC50) in air and median effective concentration (EC50) for the induction of neurobehavioral changes including seizures. We will optimize the parameters of nicotine delivery to ensure the time course of blood nicotine concentrations in rodents resembles the pharmacokinetic profile in human blood when smoking cigarettes. Aim 2. Design and engineer the nicotine delivery systems for rodents with the method developed. The exposure systems will provide two options: a restraint exposure system for accurate and acute nicotine studies, and free-moving exposure systems inside home cages for chronic studies. These systems will be incorporated into the SmartCageTM platform developed by our Company that can automatically and quantitatively monitor rodent behavior during nicotine exposure, a powerful tool for addiction studies. This Phase I project will develop a noninvasive and effective method to administer nicotine to rodents, thereby creating animal models that closely resemble the time course and magnitude of nicotine blood concentrations in humans smoking cigarettes. We will provide an important tool for studying the acute nicotine effects of smoking cigarettes and chronic effects using home cages. This method will have a significant impact on the field of tobacco-related disease and nicotine addiction research. This study will have important implications in nicotine replacement therapy (NRT) for smoking cessation. This Phase I project will lay the groundwork for a Phase II project developing a commercial product series for rats and mice, with a potential for other drugs of abuse such as marijuana, cocaine, heroin and beyond.

PUBLIC HEALTH RELEVANCE: As a result of tobacco usage, nicotine is one of the most heavily used addictive drugs and the leading preventable cause of disease, disability, and death in the U.S. The goal of the proposed project is to develop a toolkit to administer nicotine to rodents. Such a toolkit will ensure control over the amount of nicotine entering circulation and the brain, allowing for the design of experiments in which the effects of nicotine in humans may be more accurately modeled. This method will provide a powerful tool for animal research to understand the numerous effects of nicotine on the brain and body. Furthermore, this method will serve as a platform to develop more effective and safer medications for smoking cessation and treatment of tobacco-related diseases.

R43DA031578

2011-04-01

2012-07-31