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Corticostriatal circuits are key substrates for relapse, yet the role of the secondary motor cortex (M2) and its distinct projections to the dorsolateral striatum (DLS) and dorsomedial striatum (DMS) remains poorly understood. Here, we combined intravenous self-administration, pathway-selective optogenetic inhibition, and ex vivo patch-clamp recordings to measure comprehensive synaptic responses during withdrawal. Relative to withdrawal day 1, rats exhibited cocaine seeking incubation on withdrawal day 45, which was therefore selected as the primary experimental time point. Whole-cell recordings revealed heightened intrinsic excitability of M2 cortical pyramidal neurons and increased frequency, but not amplitude, of spontaneous excitatory postsynaptic currents (sEPSCs) in both DLS and DMS medium-sized spiny neurons (MSNs), suggesting the possibility of enhanced presynaptic glutamate release. Optogenetic inhibition of eNpHR-expressing M2 terminals produced opposite behavioral outcomes: suppression of cocaine seeking when targeted to the DLS, but paradoxical enhancement when targeted to the DMS. In cocaine-exposed, but not saline, rats, optogenetic inhibition increased sEPSC frequency in both DLS and DMS MSNs, suggesting altered integration of M2 or local inhibitory inputs and non-M2 excitatory afferents. Inhibitory adaptations diverged across striatal subregions: in the DLS, repeated inhibition persistently increased spontaneous inhibitory postsynaptic current (sIPSC) frequency, whereas in the DMS, sIPSC enhancement was transient, with frequency and amplitude increasing only during the first light-on period, but amplitude rapidly declined thereafter. Together, these findings suggest that M2-striatal projections contribute in a pathway-specific manner to relapse vulnerability and are associated with alterations in excitatory-inhibitory balance within M2-DLS and M2-DMS circuits.<\/jats:p>","DOI":"10.1038\/s41386-026-02385-3","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T11:14:52Z","timestamp":1774437292000},"page":"2206-2216","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Contrasting roles of secondary motor cortex projections to the dorsolateral and dorsomedial striatum in incubation of cocaine-seeking"],"prefix":"10.1038","volume":"51","author":[{"given":"V\u00edctor","family":"G\u00f3mez-Pineda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6541-240X","authenticated-orcid":false,"given":"Changyong","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3735-8412","authenticated-orcid":false,"given":"Yao-Ying","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"2385_CR1","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/35084134","volume":"412","author":"JW Grimm","year":"2001","unstructured":"Grimm JW, Hope BT, Wise RA, Shaham Y. Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature. 2001;412:141\u20132.","journal-title":"Nature"},{"key":"2385_CR2","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.bbr.2009.09.015","volume":"207","author":"Y Yalachkov","year":"2010","unstructured":"Yalachkov Y, Kaiser J, Naumer MJ. Sensory and motor aspects of addiction. Behav Brain Res. 2010;207:215\u201322.","journal-title":"Behav Brain Res"},{"key":"2385_CR3","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-37045-3","volume":"14","author":"L Wang","year":"2023","unstructured":"Wang L, Gao M, Wang Q, Sun L, Younus M, Ma S, et al. Cocaine induces locomotor sensitization through a dopamine-dependent VTA-mPFC-FrA cortico-cortical pathway in male mice. 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Psychopharmacol. 2006;189:1\u201316.","journal-title":"Psychopharmacol"},{"key":"2385_CR6","doi-asserted-by":"publisher","first-page":"2965","DOI":"10.1523\/JNEUROSCI.1728-18.2018","volume":"39","author":"VL Corbit","year":"2019","unstructured":"Corbit VL, Manning EE, Gittis AH, Ahmari SE. Strengthened inputs from secondary motor cortex to striatum in a mouse model of compulsive behavior. J Neurosci. 2019;39:2965\u201375.","journal-title":"J Neurosci"},{"key":"2385_CR7","doi-asserted-by":"publisher","unstructured":"Chen Y, Fu H, Korada A, Lange MA, Rayanki C, Lu T, et al. Decoding secondary motor cortex neuronal activity during cocaine self-administration: insights from longitudinal in vivo calcium imaging. 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