Project 1: Adolescents'use of amphetamine drugs is a major public health concern, as 11% of high school seniors have used methamphetamine or a pharmaceutical amphetamine taken other than for prescribed purposes (MTF, 2008). Interoception refers to sensing and processing the internal body state via afferent Cfibers, which is integrated in the insular cortex. Previous investigations have linked insular cortex functioning to aspects of addiction. However, the precise role of the interoceptive system and insular cortex in the development of substance dependence is unclear. Here, we hypothesize that the insular cortex is hyporesponsive to interoceptive stimulation, but hyper-reactive to drug cues in adolescents at risk for substance dependence based on repeated experimentation during youth. In this project, we will compare activity of the interoceptive system in response to positively and negatively valenced interoceptive and drug cue stimuli between: (1) at-risk adolescents who are current users of amphetamines, (2) resilient adolescents who are former users of amphetamines but stopped without ever meeting dependence criteria, and (3) control adolescents with no history of amphetamines use.
The aims are: (1) to determine the role of the insula in processing interoceptive information in teens at risk for amphetamine dependence, teens who appear resilient to amphetamine dependence, and healthy control adolescents;(2) to determine the role of the insula in processing cue-related information in teens at risk for amphetamine dependence, teens who have been resilient to amphetamine dependence, and healthy control adolescents;(3) to modify neuroimaging paradigms in response to Project 3 (animal studies) to better characterize the role of interoceptive circuitry in the direct posifive (high) versus negative (withdrawal/hangover) effects among teens at risk for amphetamine dependence;and (4) examine the development of the interoceptive system in adolescence by comparing adolescent controls and adult controls (from Project 2) on activation patterns to interoceptive and drug cue tasks. Together, these studies will help determine how interoceptive dysregulation plays a role in putting adolescents at risk for amphetamine use. These insights will be used in future studies aimed at altering the reactivity of the insular cortex as a way of preventing or treating substance dependence. Combining results from Projects 1 and 2 will yield important insights into the role of the insular cortex and interceptive functioning in risk for amphetamine dependence in general. Finally, the outcome of this study will prepare us for longitudinal studies of interceptive dysfunction in a P50 extension of this Center.

Public Health Relevance

Interceptive processing or how gut feelings regulate the urge to use is not well understood. Here, we examine adolescent amphetamine users, resilient adolescents (used amphetamines, but did not progress to dependence), and comparison teens on how their brains respond to stimulation of gut feelings. Understanding processing differences between these groups will points to targets for new interventions.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Exploratory Grants (P20)
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Special Emphasis Panel (ZDA1-MXS-M)
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University of California San Diego
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Stewart, Jennifer L; Juavinett, Ashley L; May, April C et al. (2015) Do you feel alright? Attenuated neural processing of aversive interoceptive stimuli in current stimulant users. Psychophysiology 52:249-62
Paulus, Martin P; Stewart, Jennifer L (2014) Interoception and drug addiction. Neuropharmacology 76 Pt B:342-50
Gowin, Joshua L; Harle, Katia M; Stewart, Jennifer L et al. (2014) Attenuated insular processing during risk predicts relapse in early abstinent methamphetamine-dependent individuals. Neuropsychopharmacology 39:1379-87
Stewart, Jennifer L; May, April C; Poppa, Tasha et al. (2014) You are the danger: attenuated insula response in methamphetamine users during aversive interoceptive decision-making. Drug Alcohol Depend 142:110-9
Mackey, Scott; Stewart, Jennifer L; Connolly, Colm G et al. (2014) A voxel-based morphometry study of young occasional users of amphetamine-type stimulants and cocaine. Drug Alcohol Depend 135:104-11
Gowin, Joshua L; Stewart, Jennifer L; May, April C et al. (2014) Altered cingulate and insular cortex activation during risk-taking in methamphetamine dependence: losses lose impact. Addiction 109:237-47
Gowin, Joshua L; Mackey, Scott; Paulus, Martin P (2013) Altered risk-related processing in substance users: imbalance of pain and gain. Drug Alcohol Depend 132:13-21
Mackey, Scott; Paulus, Martin (2013) Are there volumetric brain differences associated with the use of cocaine and amphetamine-type stimulants? Neurosci Biobehav Rev 37:300-16
Paulus, Martin P (2013) The breathing conundrum-interoceptive sensitivity and anxiety. Depress Anxiety 30:315-20
Stewart, Jennifer L; Flagan, Taru M; May, April C et al. (2013) Young adults at risk for stimulant dependence show reward dysfunction during reinforcement-based decision making. Biol Psychiatry 73:235-41

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