The interaction between aerobic exercise and drug abuse is relatively unexplored. It deserves attention because recent data suggest neuroadaptations from exercise promote learning in circuits that overlap with drug abuse. The hippocampus is an important point of intersection because it is a major locus for change from aerobic exercise and it plays a central role in contextual conditioning. Specifically, contextual cues paired with drugs trigger emotional responses related to craving and relapse. The long-term goal of this research program is to identify molecular and physiological mechanisms underlying the influence of exercise on drug-related behaviors in mice. The overall objective of this application is to develop a mouse model to study the effects of wheel running exercise on extinction of cocaine conditioned place preference, and to test one hypothesized mechanism for how exercise can influence Pavlovian drug associations. The central hypothesis is that new neurons from exercise can cause drug associations to persist if the drug is administered at a critical period in the development of the new neurons when they are preferentially recruited into learning networks. This is supported by the Preliminary Studies that show resistance to extinction of conditioned place preference for cocaine in runners as compared to sedentary animals after re-exposure to cocaine in context. The objective of this application will be accomplished by pursuing two specific aims.
Aim 1 is to identify the impact of aerobic exercise on extinction of conditioned place preference for cocaine. Based on Preliminary Studies, the working hypothesis is that exercise will either facilitate or delay extinction of conditioned place preference depending on whether drug exposure occurs before or after exercise training, in parallel with increased adult hippocampal neurogenesis in the dentate gyrus. To accomplish this aim, the order of conditioning and exercise treatments will be manipulated, and then conditioned place preference will be measured repeatedly until extinction. Animals will be injected with BrdU to label dividing cells, and the number of BrdU cells co-labeled with neuronal nuclear marker, NeuN, in the granule layer of the dentate gyrus will be used to measure neurogenesis.
Aim 2 is to determine the extent to which new neurons from exercise causally contribute to persistence of conditioned place preference for cocaine. Based on Preliminary Studies, the working hypothesis is that new neurons from exercise will function to enhance Pavlovian conditioning. This hypothesis will be directly tested by reducing neurogenesis using 2 separate methods, a transgenic mouse model and focal gamma irradiation, to determine whether new neurons are required for exercise to delay extinction of place preference. The extent to which new neurons are preferentially recruited into circuits involved in cocaine conditioning will also be determined by measuring the proportion of BrdU positive versus negative cells expressing c-Fos in response to the preference test. The project will discover mechanisms for interactions between exercise and drug abuse. This will be useful for evaluating the benefits or risks of incorporating exercise in treatment of drug abuse.

Public Health Relevance

This proposal will discover the impact of enhanced neuroplasticity from aerobic exercise on extinction of cocaine conditioned behavior in a mouse model. The project will provide useful evidence for evaluating the benefits or risks of incorporating exercise in treatment of drug abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA027487-04
Application #
8321052
Study Section
Special Emphasis Panel (ZDA1-GXM-A (05))
Program Officer
Pilotte, Nancy S
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$258,724
Indirect Cost
$90,671
Name
University of Illinois Urbana-Champaign
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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Kohman, Rachel A; Bhattacharya, Tushar K; Kilby, Chessa et al. (2013) Effects of minocycline on spatial learning, hippocampal neurogenesis and microglia in aged and adult mice. Behav Brain Res 242:17-24
Dabe, E C; Majdak, P; Bhattacharya, T K et al. (2013) Chronic D-amphetamine administered from childhood to adulthood dose-dependently increases the survival of new neurons in the hippocampus of male C57BL/6J mice. Neuroscience 231:125-35
Kohman, Rachel A; Bhattacharya, Tushar K; Wojcik, Elzbieta et al. (2013) Exercise reduces activation of microglia isolated from hippocampus and brain of aged mice. J Neuroinflammation 10:114
Kohman, Rachel A; Rhodes, Justin S (2013) Neurogenesis, inflammation and behavior. Brain Behav Immun 27:22-32
Kohman, Rachel A; Clark, Peter J; Deyoung, Erin K et al. (2012) Voluntary wheel running enhances contextual but not trace fear conditioning. Behav Brain Res 226:1-7
Clark, P J; Bhattacharya, T K; Miller, D S et al. (2011) Induction of c-Fos, Zif268, and Arc from acute bouts of voluntary wheel running in new and pre-existing adult mouse hippocampal granule neurons. Neuroscience 184:16-27
Zombeck, Jonathan A; Deyoung, Erin K; Brzezinska, Weronika J et al. (2011) Selective breeding for increased home cage physical activity in collaborative cross and Hsd:ICR mice. Behav Genet 41:571-82
Kohman, Rachel A; Rodriguez-Zas, Sandra L; Southey, Bruce R et al. (2011) Voluntary wheel running reverses age-induced changes in hippocampal gene expression. PLoS One 6:e22654

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