@article{810c0b77a44241999e90aa364e88ac60,
title = "Neurobehavioral Precursors of Compulsive Cocaine Seeking in Dual Frontostriatal Circuits",
abstract = "Background: Only some individuals who use drugs recreationally eventually develop a substance use disorder, characterized in part by the rigid engagement in drug foraging behavior (drug seeking), which is often maintained in the face of adverse consequences (i.e., is compulsive). The neurobehavioral determinants of this individual vulnerability have not been fully elucidated. Methods: Using a prospective longitudinal study involving 39 male rats, we combined multidimensional characterization of behavioral traits of vulnerability to stimulant use disorder (impulsivity and stickiness) and resilience (sign tracking and sensation seeking/locomotor reactivity to novelty) with magnetic resonance imaging to identify the structural and functional brain correlates of the later emergence of compulsive drug seeking in drug-na{\"i}ve subjects. We developed a novel behavioral procedure to investigate the individual tendency to persist in drug-seeking behavior in the face of punishment in a drug-free state in subjects with a prolonged history of cocaine seeking under the control of the conditioned reinforcing properties of a drug-paired Pavlovian conditioned stimulus. Results: In drug-na{\"i}ve rats, the tendency to develop compulsive cocaine seeking was characterized by behavioral stickiness–related functional hypoconnectivity between the prefrontal cortex and posterior dorsomedial striatum in combination with impulsivity-related structural alterations in the infralimbic cortex, anterior insula, and nucleus accumbens. Conclusions: These findings show that the vulnerability to developing compulsive cocaine-seeking behavior stems from preexisting structural or functional changes in two distinct corticostriatal systems that underlie deficits in impulse control and goal-directed behavior.",
keywords = "Addiction, Cocaine, Compulsivity, Endophenotype, Impulsivity, MRI, Stickiness",
author = "Jones, {Jolyon A.} and Aude Belin-Rauscent and Bianca Jupp and Maxime Fouyssac and Sawiak, {Stephen J.} and Katharina Zuhlsdorff and Peter Zhukovsky and Lara Hebdon and {Velazquez Sanchez}, Clara and Robbins, {Trevor W.} and Everitt, {Barry J.} and David Belin and Dalley, {Jeffrey W.}",
note = "Funding Information: TWR is a consultant for Cambridge Cognition and has received grants from GlaxoSmithKline and Shionogi Inc. and royalties from Cambridge Cognition. JWD has received research grants from GlaxoSmithKline and Boehringer Ingelheim Pharma GmbH. DB has received research funding from Shionogi Inc. BJE has received research funding from GlaxoSmithKline. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the Medical Research Council (Grant No. MR/N02530X/1 [to BJE, DB, JWD, TWR]); a Medical Research Council Doctoral Training Programme scholarship (to JAJ); the AXA Research Fund (to BJ), the National Health and Medical Research Council of Australia, and the Cambridge Newton Trust (to BJ); and a studentship from the Pinsent Darwin Trust in Cambridge (to PZ). Cocaine hydrochloride was provided by the National Institute on Drug Abuse Drug Supply Program (to DB). JWD, DB, JAJ, AB-R, TWR, BJE, and BJ contributed to the experimental design. JAJ, LH, BJ, CVS, and PZ contributed to behavioral screening. JAJ, BJ, PZ, and SJS performed the imaging experiments. JAJ, CVS, and SJS analyzed the structural imaging data. JAJ analyzed the functional imaging data. JAJ, DB, KZ, PZ, AB-R, and MF performed the analysis of the behavioral data. DB performed the intravenous catheter surgeries. AB-R performed self-administration training with support from JAJ and BJ. MF and AB-R analyzed the cocaine self-administration data. MF and DB designed and validated the compulsive drug-seeking procedure. MF carried out the pain sensitivity experiment on an independent cohort. JAJ, JWD, DB, TWR, and BJE wrote the manuscript. All authors contributed to editing the manuscript. A previous version of this article was published as a preprint on bioRxiv: https://www.biorxiv.org/content/10.1101/2022.11.09.515779v1. TWR is a consultant for Cambridge Cognition and has received grants from GlaxoSmithKline and Shionogi Inc. and royalties from Cambridge Cognition. JWD has received research grants from GlaxoSmithKline and Boehringer Ingelheim Pharma GmbH. DB has received research funding from Shionogi Inc. BJE has received research funding from GlaxoSmithKline. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the Medical Research Council (Grant No. MR/N02530X/1 [to BJE, DB, JWD, TWR] ); a Medical Research Council Doctoral Training Programme scholarship (to JAJ); the AXA Research Fund (to BJ) , the National Health and Medical Research Council of Australia, and the Cambridge Newton Trust (to BJ); and a studentship from the Pinsent Darwin Trust in Cambridge (to PZ). Cocaine hydrochloride was provided by the National Institute on Drug Abuse Drug Supply Program (to DB). Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2024",
month = jan,
doi = "10.1016/j.bpsgos.2023.06.001",
language = "English",
volume = "4",
pages = "194--202",
journal = "Biological Psychiatry: Global Open Science",
issn = "2667-1743",
publisher = "Elsevier",
number = "1",
}
