Project 3: Substance abuse and dependence are enormous societal problems, with lifetime prevalence in adults greater than 15% in the United States. Despite significant recent advances in identifying critical neurobiological mechanisms underlying addiction, high rates of recidivism are seen with most biologically based treatments of substance dependence developed to date. Here we propose to examine the relatively unexplored role of interoception, the internal sense of the body, in regulation of drug-related urges, to provide a new conceptual framework from which novel treatment strategies may emerge. The overall goal of CIDIA is to elucidate the role of interoception in addiction, and Project 3 in particular examines the role of insular cortex for regulating drug-induced alterations in hedonic processing, potentially providing novel targets for addiction treatment. This animal project uses a direct insular cortex manipulation, "silencing" of rostral (agranular) or caudal (granular/dysgranular) insula through excessive inhibition with the GABAa agonist muscimol, to examine the causal role of interoceptive processing in: (1) the direct rewarding ("euphorigenic") effects of d-amphetamine and morphine as measured by brain reward thresholds;(2) the "dysphorigenic" effects of withdrawal from acute or chronic dependence on these drugs as measured by brain reward thresholds;(3) the conditioned (learned) association between a novel environment paired with acute drug reward or withdrawal aversion as measured in a place conditioning paradigm. In this way, the animal study complements the human neuroimaging experiments of Projects 1 and 2 by ascertaining whether disruption of insula function alters hedonic processing along multiple dimensions: (1) positive (reward, euphoria) versus negative affect (aversion, dysphoria);(2) across time from initial drug exposure (acute reward and acute withdrawal) to chronic dependence;(3) direct versus conditioned hedonic processes;and (4) stimulant versus opioid effects. The results of these experiments will be used in the human projects to modify the neuroimaging paradigms to examine whether these differences can be observed in subjects in different stages of drug addiction. For example, the experimental paradigms used in Wave 2 of Projects 1 and 2 are contingent on Project 3 outcomes of insula silencing on positive versus negative direct / indirect reward-related effects. Importantly, the animal model will provide a causal test of the cross-sectional human imaging findings, which are correlational by nature. Finally, converging validity in both animal and human studies can lay the groundwork for a pre-clinical platform to examine treatments.

Public Health Relevance

The role of interoceptive processing in addiction, or how gut feelings regulate the urge to use, is not well understood. The animal studies of Project 3 of this center proposal provide a causal assessment of the insula's importance to various elements of hedonic processing known to be critical to initiation and escalation of drug use, maintenance of compulsive use, and relapse after attempted abstinence. Results will help identify new potential targets for prevention and treatment of drug dependence.

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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Squeglia, Lindsay M; Ball, Tali M; Jacobus, Joanna et al. (2016) Neural Predictors of Initiating Alcohol Use During Adolescence. Am J Psychiatry :appiajp201615121587
Paulus, Martin P; Huys, Quentin J M; Maia, Tiago V (2016) A Roadmap for the Development of Applied Computational Psychiatry. Biol Psychiatry Cogn Neurosci Neuroimaging 1:386-392
Mackey, Scott; Olafsson, Valur; Aupperle, Robin L et al. (2016) Greater preference consistency during the Willingness-to-Pay task is related to higher resting state connectivity between the ventromedial prefrontal cortex and the ventral striatum. Brain Imaging Behav 10:730-8
Berk, Lotte; Stewart, Jennifer L; May, April C et al. (2015) Under pressure: adolescent substance users show exaggerated neural processing of aversive interoceptive stimuli. Addiction 110:2025-36
Oosterwijk, Suzanne; Mackey, Scott; Wilson-Mendenhall, Christine et al. (2015) Concepts in context: Processing mental state concepts with internal or external focus involves different neural systems. Soc Neurosci 10:294-307
Gowin, Joshua L; Ball, Tali M; Wittmann, Marc et al. (2015) Individualized relapse prediction: Personality measures and striatal and insular activity during reward-processing robustly predict relapse. Drug Alcohol Depend 152:93-101
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

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