{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:31:57Z","timestamp":1760146317030,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T00:00:00Z","timestamp":1730160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32271137"],"award-info":[{"award-number":["32271137"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CAS Key Laboratory of Mental Health, Institute of Psychology","award":["32271137"],"award-info":[{"award-number":["32271137"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The reinforcement of drug-seeking motivation following drug withdrawal is recognized as a significant factor contributing to relapse. The ventral pallidum (VP) plays a crucial role in encoding and translating motivational aspects of reward. However, current research lacks a clear understanding of how the VP mediates drug-seeking motivation and the feedback modulation between the VP and the nucleus accumbens (NAc) following drug withdrawal. Therefore, utilizing a rat model of cocaine self-administration, we investigated the circuitry mechanisms underlying drug-seeking behavior post-drug withdrawal involving the NAc-VP pathway. Initially, we observed a significant enhancement in drug-seeking behavior 14 days after cocaine withdrawal. Subsequently, we identified the feedback mechanism through which the NAc-VP regulates this behavior. Immunofluorescence results indicated an increase in c-Fos expression levels in the ventral pallidum ventromedial (VPvm) and ventrolateral ventral pallidum (VPvl) following drug withdrawal. Calcium fiber photometry further elucidated that during the expression of high motivational drug-seeking behavior, there was a specific enhancement in VPvm neuronal activity, and retrograde tracing techniques suggested a weakened transmission function in the NAc-VPm pathway. Additionally, chemical genetic techniques demonstrated that inhibiting the activity of the NAc-VP pathway could increase the motivational level of drug-seeking behavior. These findings indicate that the reduced inhibitory function of the NAc-VP pathway following prolonged cocaine withdrawal forms the basis for heightened reactivity in VPvm neurons, thus regulating the expression of high motivational behavior triggered by drug-related cues. Our study results suggest that maintaining normal NAc-VP pathway functionality may decrease drug-seeking motivation post long-term drug withdrawal, offering new insights for interventions targeting relapse.<\/jats:p>","DOI":"10.3390\/ijms252111612","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T06:29:57Z","timestamp":1730183397000},"page":"11612","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Mechanism of the Nucleus Accumbens\u2013Ventral Pallidum Pathway Mediated by Drug Withdrawal-Induced High-Seeking Motivation in Cocaine Addiction"],"prefix":"10.3390","volume":"25","author":[{"given":"Jiayan","family":"Tan","sequence":"first","affiliation":[{"name":"Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, No. 16 Lin Cui Road, Beijing 100101, China"},{"name":"Department of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiming","family":"Meng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, No. 16 Lin Cui Road, Beijing 100101, China"},{"name":"Department of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenjie","family":"Du","sequence":"additional","affiliation":[{"name":"Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, No. 16 Lin Cui Road, Beijing 100101, China"},{"name":"Department of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingtong","family":"Jin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, No. 16 Lin Cui Road, Beijing 100101, China"},{"name":"Department of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Liang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, No. 16 Lin Cui Road, Beijing 100101, China"},{"name":"Department of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9486-304X","authenticated-orcid":false,"given":"Fang","family":"Shen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, No. 16 Lin Cui Road, Beijing 100101, China"},{"name":"Department of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1001\/jamapsychiatry.2016.2181","article-title":"Incubation of Cue-Induced Craving in Adults Addicted to Cocaine Measured by Electroencephalography","volume":"73","author":"Parvaz","year":"2016","journal-title":"JAMA Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1176\/appi.ajp.162.8.1403","article-title":"The Neural Basis of Addiction: A Pathology of Motivation and Choice","volume":"162","author":"Kalivas","year":"2005","journal-title":"Am. 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