Adolescent exposure to social stress is associated with a greater incidence of psychiatric and substance abuse disorders, but it is not known how neural mechanisms are altered by adolescent social stress to result in psychopathologies. We have developed a rat model of adolescent social defeat to investigate detrimental effects of teenage bullying, one of the most common social stressors experienced by humans worldwide. As adults, previously defeated rats exhibit decreased medial prefrontal cortex (mPFC) dopamine (DA) tissue content and dampened amphetamine-evoked extracellular mPFC DA release. Adult rats previously exposed to adolescent social defeat also show increased behavioral responses to amphetamine, including greater amphetamine-induced locomotion and a higher preference for amphetamine-associated cues. In this proposal, we will test the hypothesis that mPFC DA hypofunction following adolescent defeat exposure causes heightened amphetamine sensitivity in adulthood. We will also test whether increased amphetamine sensitivity following adolescent social stress can be prevented through pharmacological manipulations delivered at different time points: either (1) by blocking disruption to mPFC DA during the adolescent stress experience, or (2) by restoring mPFC DA activity after stress exposure. The novel use of this animal model to examine these questions provides an innovative means of establishing for the first time a direct link between adolescent stress, mPFC DA function and enhanced sensitivity to drugs of abuse. The proposed research will provide important information for the development of pharmacotherapeutic strategies for treating addiction disorders resulting from exposure to bullying stress in adolescence. Positive findings will also identify the mPFC DA system as an important mediator of adolescent stress-induced behavioral dysfunction. Given the pivotal role of the mPFC in cognition and top-down regulation of emotion, this has broad application for directing potential therapies for disorders that result from adolescent stress beyond addiction. In addition to addressing an important scientific problem, the current proposal will also enrich student research experiences at the University of South Dakota. These studies will provide students with meaningful and high quality early training opportunities in neurobiology, neuropharmacology and behavioral neuroscience in a rural state that is under- represented in terms of federally funded scientific research. The end result will enhance the research training environment at USD and increase the prospects for students from South Dakota to pursue a future career in health-related sciences.

Public Health Relevance

Exposure to social stress during adolescence is associated with various adult psychopathologies, including substance abuse disorder. The proposed research will identify neurochemical mechanisms linking social stress in adolescence with later sensitivity to drugs of abuse, with a focus on cortical dopamine dysfunction. Information gained from these studies will further the understanding of the long-term effects of adolescent social stress on the brain and drug-related behaviors, and will assist in directing the clinical applicatin of existing and new pharmacotherapies to counteract these deleterious effects of adolescent stress.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15DA035478-01A1
Application #
8688582
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Lynch, Minda
Project Start
2014-06-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2017-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$422,997
Indirect Cost
$122,997
Name
University of South Dakota
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
929930808
City
Vermillion
State
SD
Country
United States
Zip Code
57069