The goal of this component of the POI application is to develop methods to evaluate the relative abuse liability of tobacco products in animals. The tobacco industry is introducing several """"""""modified risk"""""""" tobacco products (MRTPs) promoted to be safer or less addictive than conventional products. The Food and Drug Administration (FDA) is now required to evaluate the abuse liability of current and future MRTPs. Animal models are urgently needed for this process because they allow a) examination of critical phenomena that cannot be studied experimentally in humans (e.g., initiation of tobacco use in adolescents), b) isolation of the role of nicotine and other tobacco constituents from other factors, and c) screening of novel tobacco formulations prior to human exposure. Current animal models that only examine nicotine or other isolated constituents may not accurately assess the abuse liability of tobacco products because a) as yet unidentified compounds may contribute (positively or negatively) to tobacco abuse and b) it is the interaction of these compounds that determines the actual abuse liability of a product. The current project will address this issue by using well-established animal models to examine the abuse liability of aqueous tobacco extracts from four different MRTPs and a conventional product. These extracts provide an extensive range of nicotine and other tobacco constituents to more closely model actual product exposure in humans.
Aim la will compare the reinforcing efficacy of tobacco extracts and nicofine with intravenous self-administration (SA) models using behavioral economic methods Aim lb will compare acquisifion of extract and nicofine SA in adolescent and adult rats.
Aim 1 c will compare extracts and nicotine in terms of their reinforcement-enhancing and aversive effects measured as changes in intracranial self-stimulation (ICSS) thresholds.
Aim 2 will compare the ability of chronic infusion of extracts and nicofine to induce dependence as measured by withdrawal-induced elevafions in ICSS thresholds. Because some non-nicotine constituents are known to enhance nicotine's dependence-related effects, the general working hypothesis is that tobacco extracts will have greater abuse liability than equivalent doses of pure nicotine. We also hypothesize that the proposed methods will be sufficiently sensifive to disfinguish between extracts of different products. The proposed studies were specifically designed to parallel the human studies in this POI by a) employing behavioral economic methods to assess reinforcing efficacy, b) measuring withdrawal severity, and c) examining some of the same products. As such, this POI will allow validation of behavioral economics as a framework for integrating findings across species and predicting populafion-level abuse of different products. Examining abuse liability in adolescents will provide a critical extension of the human projects. By studying several more products than the human studies, findings in animals may help prioritize other products that need to be evaluated in humans. This study will provide the basis for standardized animal models of abuse liability to evaluate tobacco products and inform FDA regulafion of performance standards.

Public Health Relevance

The FDA is now required to evaluate and regulate tobacco products toward the goal of protecting public health. This study will develop animal models to assess the relative abuse liability of several tobacco products using aqueous extracts of those products that provide a range of constituents similar to product exposure in humans. In concert with humans studies in this POI, these models may be useful for anficipafing the likelihood and extent of population-level abuse of new tobacco products in humans and its associated impact on public health. They may also help understand how chemicals other than nicotine contribute to tobacco addiction and suggest relevant performance standards for tobacco products to limit or reduce their addictiveness.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19CA157345-01A1
Application #
8310407
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (J1))
Project Start
2012-09-01
Project End
2017-08-31
Budget Start
2012-09-20
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$285,304
Indirect Cost
$33,850
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Bickel, Warren K; Mellis, Alexandra M; Snider, Sarah E et al. (2018) 21st century neurobehavioral theories of decision making in addiction: Review and evaluation. Pharmacol Biochem Behav 164:4-21
Harris, Andrew C; Muelken, Peter; Haave, Zach et al. (2018) Propylene glycol, a major electronic cigarette constituent, attenuates the adverse effects of high-dose nicotine as measured by intracranial self-stimulation in rats. Drug Alcohol Depend 193:162-168
Ho, Yen-Yi; Nhu Vo, Tien; Chu, Haitao et al. (2018) A Bayesian hierarchical model for demand curve analysis. Stat Methods Med Res 27:2038-2049
Stein, Jeffrey S; Heckman, Bryan W; Pope, Derek A et al. (2018) Delay discounting and e-cigarette use: An investigation in current, former, and never cigarette smokers. Drug Alcohol Depend 191:165-173
Bunney, Patricia E; Hansen, Mylissa; LeSage, Mark (2018) Effects of isolated tobacco alkaloids and tobacco products on deprivation-induced food intake and meal patterns in rats. Pharmacol Biochem Behav 165:45-55
LeSage, Mark G; Smethells, John R; Harris, Andrew C (2018) Status and Future Directions of Preclinical Behavioral Pharmacology in Tobacco Regulatory Science. Behav Anal (Wash D C) 18:252-274
Berman, Micah L; Hatsukami, Dorothy K (2018) Reducing tobacco-related harm: FDA's proposed product standard for smokeless tobacco. Tob Control 27:352-354
Stein, Jeffrey S; Koffarnus, Mikhail N; Stepanov, Irina et al. (2018) Cigarette and e-liquid demand and substitution in e-cigarette-naïve smokers. Exp Clin Psychopharmacol 26:233-243
Harris, Andrew C; Muelken, Peter; Smethells, John R et al. (2018) Effects of nicotine-containing and ""nicotine-free"" e-cigarette refill liquids on intracranial self-stimulation in rats. Drug Alcohol Depend 185:1-9
Smethells, John R; Harris, Andrew C; Burroughs, Danielle et al. (2018) Substitutability of nicotine alone and an electronic cigarette liquid using a concurrent choice assay in rats: A behavioral economic analysis. Drug Alcohol Depend 185:58-66

Showing the most recent 10 out of 58 publications