Maury Cole - US grants

At present, investigators who want to expose laboratory rodents to alcohol can inject the drug, feed it through a chocolate-base diet, or deliver it in contained chambers in the form of vapors. Currently available alcohol chambers contain several cages which each house 3-6 rodents. The purpose of this Phase I feasibility study is to show that we can build smaller chambers in which laboratory rodents (primarily rats or mice) are exposed to alcohol vapors under tightly controlled conditions. The proposed chambers will house 1-4 rats or 3-6 mice, depending on weights. This prototype has two main advantages over presently available methods. First, each chamber can be individually controlled, which means that target blood alcohol levels (BALs) can be finely regulated. Second, the animals can be equipped with permanent intravenous or intracerebroventricular cannulae to samples biological fluids and/or inject treatments without manipulating the animals or opening the chambers. Over the past 8 months, we have built 6 such cages to demonstrate that most of the problems encountered should be solvable, provided we have the appropriate resources. These problems include the presence of condensation, the maintenance of environmentally safe chambers (i.e. from which no alcohol vapors, escape) despite the presence of portholes for the passage of the cannulae, and the adequacy of standard air sources commonly available in the laboratory to propel the alcohol vapors through the system. The objectives that need to be reached under Phase I are (1) to automate the system, which is presently cumbersome and labor-intensive, (2) to bring the problem of condensation to its final solution, (3) to ensure that the final parameters of air velocity do not lead to the release of ACTH and corticosterone, taken as indexes of stress, and (4) to demonstrate that the prototype can be extended to at least 12 chambers. Once the prototype is finalized, the investigator will be provided with a pre-assembled set of cages with all necessary components, and charts that will enable him/her to reach the target BALs on the basis of the animal's weight The long-term commercial objectives, however, are to build a system that can be used not only to deliver alcohol, but also toxic substances that need to be contained, such as nicotine, carcinogens, etc. We therefore believe that the prototype for which we want to demonstrate feasibility, will be attractive to a wide variety of researchers who need environmentally safe and easy to use devices to study the effects of these substances. PROPOSED COMMERCIAL APPLICATIONS: On the basis of numerous conversations with colleagues, as well as our own experience in the field, we have no doubt that such a device would find a ready market and thus have excellent commercial potential. There are many investigators who expose rodents to alcohol, and all those who do not require voluntary drug intake will welcome an easy-to-use, reliable, flexible and affordable device to do so, which does not require extensive labor. In addition, this technology can be used to expose animals to reagents other than alcohol, that need to be contained such as nicotine, carcinogens, pollutants, potential irritants, etc. This provides a major advance in the field of toxicology.

? DESCRIPTION (provided by applicant): This SBIR Phase II proposal will enhance the pace of development and support the eventual commercialization of a self-administration vapor inhalation chamber system for the intrapulmonary delivery to rats of ?9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis. Cannabis remains the most popular illicit psychoactive drug used in the US. Some 70-80% of 40-50 year olds have tried cannabis at least once in their lifetime and 18-19% of 18-21 year olds have used cannabis in the past month. There are more people in the US who meet criteria for cannabis dependence than have used cocaine in the past month or ever tried heroin. It is of further concern that the use of cannabis under medical marijuana laws continues to expand. Further mechanistic understanding of how dependence of THC develops and the discovery of therapeutics is an increasingly critical goal, yet progress has been slowed by the failure of rats to readily self-administer THC by the traditional intravenous route. The studies in this project seek to further refine our instrumentation to create a reliable rat model of THC self-administration via vapor inhalation. Studies under Specific Aim 1 will assess the pharmacokinetic distribution of THC as well as effects of intrapulmonary exposure on thermoregulation, locomotor activity, catalepsy, and analgesia, to determine necessary exposure parameters. The goal is to achieve well-controlled exposure under a broad range of plasma THC levels which range from threshold of behavioral effects to doses which can produce dependence with repeated exposure. Studies under Aim 2 will establish dependence on THC as well as operant self-administration using delivery of volatilized THC as a reinforcer. Studies under Aim 3 will test specific instrumentation design changes dictated by Aims 1 and 2, as well as by the preliminary data detailed in the Research Strategy.

Project Summary This Phase II SBIR project will develop, optimize, test, commercialize, and take to market an inhalation chamber that mimics the e-cigarette technology being used by human users, and being popularized by e- cigarette manufacturers and advertisers. E-cigarette use and abuse is a major public health concern, but little is known about the biology underlying e-cigarette use and negative health impact of e-cigarettes, which makes it difficult for government agencies to regulate these products. Current animal models are inadequate for examining the biological effects and addictive properties of e-cigarettes in a model that delivers vapor to animals in the same way humans self-administer it. Therefore, the major purpose of this proposal is to develop a nicotine e-cigarette vapor instrument to fill this gap in the market and in the e-cigarette research field. Our general approach will be to develop and install design modifications to our current vapor administration systems that include changes to hardware (Aims 1&2), software and user interface (Aim 3), and vaporized solutions (Aim 4), and each of these design modifications will be tested in rats. Comprehensive dosage charts will be developed as part of Aim 4. This phase II SBIR application proposes work that will be critical for developing and optimizing a device that allows for nicotine vapor self-administration in rodents, using the identical technology and route of delivery experienced by human users. The marketability for this type of device is high because there is no such device currently on the market, and also because this research area is a high funding priority for government agencies. Therefore, our major goal is to develop and market a device that allows for customizable and reliable e-cigarette vapor self-administration in rats.