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Compulsive drug use, a hallmark of substance use disorder, is attributed to maladaptive decision-making regarding aversive drug-use-related events and has been associated with dysregulation of various frontal\u2013midbrain circuits. To\u00a0understand the contributions of frontal\u2013habenula\u2013midbrain circuits in the development of drug dependence, we employed a rat model of methamphetamine self-administration (SA) in the presence of concomitant footshock, which has been proposed to model compulsive drug-taking in humans. In this longitudinal study, functional MRI data were collected at pretraining baseline, after 20 d of long-access SA phase, and after 5 d of concomitant footshock coupled with SA (punishment phase). Individual differences in response to punishment were quantified by a \u201ccompulsivity index (CI),\u201d defined as drug infusions at the end of punishment phase, normalized by those at the end of SA phase. Functional connectivity of LHb with the frontal cortices and substantia nigra (SN) after the punishment phase was positively correlated with the CI in rats that maintained drug SA despite receiving increasing-intensity footshock. In contrast, functional connectivity of the same circuits was negatively correlated with CI in rats that significantly reduced SA. These findings suggest that individual differences in compulsive drug-taking are reflected by alterations within frontal\u2013LHb\u2013SN circuits after experiencing the negative consequences from SA, suggesting these circuits may serve as unique biomarkers and potential therapeutic targets for individualized treatment of addiction.<\/jats:p>","DOI":"10.1073\/pnas.2208867119","type":"journal-article","created":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T15:13:32Z","timestamp":1670253212000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":15,"title":["Compulsive drug-taking is associated with habenula\u2013frontal cortex connectivity"],"prefix":"10.1073","volume":"119","author":[{"given":"Ying","family":"Duan","sequence":"first","affiliation":[{"name":"Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Jung","family":"Tsai","sequence":"additional","affiliation":[{"name":"Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betty Jo","family":"Salmeron","sequence":"additional","affiliation":[{"name":"Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuzheng","family":"Hu","sequence":"additional","affiliation":[{"name":"Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224"},{"name":"Department of Psychology and Behavioral Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. 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