Drug addiction exacts a substantial toll on the economic, social, and medical systems in this country. The biology of brain reward systems mediating the reinforcing property of drugs is relatively well understood, but hedonic properties alone fail to explain why some individuals progress to uncontrolled drug taking and others do not. A complete understanding of addiction requires a shift in focus to negative reinforcement models in which a compulsion to take drugs is driven by the need to terminate or avoid an aversive state. The aversive state may be somatic or affective. Little is known about neural mechanisms of negative reinforcement. Animal studies suggest that negative learning involves not only opponent processes within the same reward-related systems but may also involve distinct neural structures and signals. It is clear that there are cognitive and behavioral impairments in motivational affect, inhibitory control, and frontal executive function in substance dependent individuals (SDI). The overall goal of this application is to elucidate mechanisms underlying negative motivational affective state and negative reinforcement learning deficits in SDI. This will be accomplished using functional MRI (fMRI) and a reinforcement learning paradigm based on the Iowa Gambling Task. We will show that the paradigm is sensitive to deficits in negative and positive reinforcement learning in SDI. We will study abstinent SDI and healthy controls matched for education, IQ, and age, to address 3 specific aims:
Aim 1. Determine if there is a deficit in negative reinforcement learning in SDI compared to controls. If so, determine if this deficit is associated with a negative affective state.
Aim 2. Determine the neural pathways involved in negative and positive reinforcement learning Aim 3. Determine if frontal-limbic activity differs in SDI compared to controls during negative and positive reinforcement learning

Public Health Relevance

This application is relevant to public health because of the substantial direct and indirect costs related to licit and illicit drugs in this country. A significant gap in knowledge exists about what factors differentiate controlled use from uncontrolled addiction. This project will address that gap by studying addiction in terms of a negative reinforcement model that may better explain the critical transition from initial impulsive to chronic compulsive drug use.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZDA1-KXH-C (07))
Program Officer
Kautz, Mary A
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University of Colorado Denver
Schools of Medicine
United States
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Yamamoto, Dorothy J; Banich, Marie T; Regner, Michael F et al. (2017) Behavioral approach and orbitofrontal cortical activity during decision-making in substance dependence. Drug Alcohol Depend 180:234-240
Lind, Kimberly E; Gutierrez, Eric J; Yamamoto, Dorothy J et al. (2017) Sex disparities in substance abuse research: Evaluating 23 years of structural neuroimaging studies. Drug Alcohol Depend 173:92-98
Regner, Michael F; Saenz, Naomi; Maharajh, Keeran et al. (2016) Top-Down Network Effective Connectivity in Abstinent Substance Dependent Individuals. PLoS One 11:e0164818
Krmpotich, Theodore; Mikulich-Gilbertson, Susan; Sakai, Joseph et al. (2015) Impaired Decision-Making, Higher Impulsivity, and Drug Severity in Substance Dependence and Pathological Gambling. J Addict Med 9:273-80
Chumachenko, Serhiy Y; Sakai, Joseph T; Dalwani, Manish S et al. (2015) Brain cortical thickness in male adolescents with serious substance use and conduct problems. Am J Drug Alcohol Abuse 41:414-24
Regner, Michael F; Dalwani, Manish; Yamamoto, Dorothy et al. (2015) Sex Differences in Gray Matter Changes and Brain-Behavior Relationships in Patients with Stimulant Dependence. Radiology 277:801-12
Yamamoto, Dorothy J; Woo, Choong-Wan; Wager, Tor D et al. (2015) Influence of dorsolateral prefrontal cortex and ventral striatum on risk avoidance in addiction: a mediation analysis. Drug Alcohol Depend 149:10-7
Yamamoto, Dorothy J; Reynolds, Jeremy; Krmpotich, Theodore et al. (2014) Temporal profile of fronto-striatal-limbic activity during implicit decisions in drug dependence. Drug Alcohol Depend 136:108-14
Perry, Robert I; Krmpotich, Theodore; Thompson, Laetitia L et al. (2013) Sex modulates approach systems and impulsivity in substance dependence. Drug Alcohol Depend 133:222-7
Tanabe, J; York, P; Krmpotich, T et al. (2013) Insula and orbitofrontal cortical morphology in substance dependence is modulated by sex. AJNR Am J Neuroradiol 34:1150-6

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