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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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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