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 addicfion, 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 interocepfion, the internal sense of the body, in regulafion 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 addicfion, and Project 3 in particular examines the role of insular cortex for regulating drug-induced alterations in hedonic processing, potentiallv 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 inhibifion with the GABAa agonist muscimol, to examine the causal role of interocepfive 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) associafion 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 mulfiple dimensions: (1) posifive (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 condifioned 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.
The role of interoceptive processing in addicfion, 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 crifical to initiafion and escalafion of drug use, maintenance of compulsive use, and relapse after attempted absfinence. Results will help identify new potential targets for prevention and treatment of drug dependence.
|Blair, Melanie A; Stewart, Jennifer L; May, April C et al. (2018) Blunted Frontostriatal Blood Oxygen Level-Dependent Signals Predict Stimulant and Marijuana Use. Biol Psychiatry Cogn Neurosci Neuroimaging 3:947-958|
|Huang, He; Thompson, Wesley; Paulus, Martin P (2017) Computational Dysfunctions in Anxiety: Failure to Differentiate Signal From Noise. Biol Psychiatry 82:440-446|
|Gowin, Joshua L; May, April C; Wittmann, Marc et al. (2017) Doubling down: increased risk-taking behavior following a loss by individuals with cocaine use disorder is associated with striatal and anterior cingulate dysfunction. Biol Psychiatry Cogn Neurosci Neuroimaging 2:94-103|
|Gowin, Joshua L; Ball, Tali M; Wittmann, Marc et al. (2017) Corrigendum to ""Individualized relapse prediction: Personality measures and striatal and insular activity during reward-processing robustly predict relapse"" [Drug and Alcohol Dependence 152 (2015) 93-101]. Drug Alcohol Depend 175:255|
|Squeglia, Lindsay M; Ball, Tali M; Jacobus, Joanna et al. (2017) Neural Predictors of Initiating Alcohol Use During Adolescence. Am J Psychiatry 174:172-185|
|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|
|Harlé, Katia M; Zhang, Shunan; Ma, Ning et al. (2016) Reduced Neural Recruitment for Bayesian Adjustment of Inhibitory Control in Methamphetamine Dependence. Biol Psychiatry Cogn Neurosci Neuroimaging 1:448-459|
|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|
|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|
Showing the most recent 10 out of 31 publications