This application requests initial support for an Exploratory Center for Translational Research on the Clinical Neurobiology of Drug Addiction (P20). The proposed UCSD Center on Interoceptive Dysregulation in Addiction (CIDIA) addresses the global question: "How does the brain regulate the urge to use?", with a focus initially on "What is the role of interoceptive systems in general, and insular cortex in particular, in amphetamine addiction?" Interoception comprises sensing the physiological condition of the body, the conscious representation of this internal state within the context of ongoing activities, and the initiation of motivated action to regulate this state. Recent human and animal findings provide compelling evidence that interoceptive processing in the insula may mediate drug-related urges and preferences. Despite this evidence, it remains unclear how exactly the insula modulates these behaviors and what role interoceptive processing plays in different stages of addiction. To address these questions, we propose the following Specific Aims: (1) To determine the response characteristics of the interoceptive system using functional magnetic resonance imaging (fMRI) in adolescents and adults across stages of amphetamine use/addiction;(2) To delineate the causal role of interoceptive processing in mediating direct and conditioned rewarding or aversive effects in a rodent model using "insula silencing" via reversible inactivation of neural activity with muscimol;and (3) To integrate results of animal and human studies and provide translational predictions by (a) developing animal models of interoceptive dysfunction, (b) using predictions from animal finding to modify human neuroimaging paradigms, and (c) modifying target structures of animal "silencing" experiments based on human imaging studies. The goal for the Center is to impact the field of drug addiction in the following ways: (1) To develop and refine our understanding of the role of interoception for amphetamine dependence and, possibly, for addiction at large;(2) To develop translational paradigms to probe the sensitivity of the interoceptive system in animal models of drug addiction and humans in different stages of drug addiction;(3) To lay the groundwork for modulating the interoceptive system as a target for treatment;and (4) To discover risk factors or phenotypes for drug addiction involving interoceptive processing.
Brain systems that sense the how you feel have recently been implicated in urge to use drugs. This center proposes to use animal experiments and human brain imaging studies to determine how these brain systems regulate the urge to use. Results from these experiments will provide (1) ways to monitor who is at high risk for developing drug addiction or who may relapse;(2) novel treatment targets for addiction.
|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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