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The dorsal raphe nucleus (DRN) serotonin (5-HT) system modulates reward- and stress-related responses, but its role in both male and female rats remains incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate the role of the DRN 5-HT system in heroin-motivated behaviors in male and female rats, and, in parallel, to examine the impacts of stress-induced reinstatement of heroin seeking on DRN 5-HT cell electrophysiological profiles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To probe DRN 5-HT contributions to basal, punished, and stress-driven heroin consumption, we performed chemogenetic manipulations in transgenic Tph2-iCre Sprague-Dawley rats. Twenty-two- and 50-kHz ultrasonic vocalizations (USVs), reflecting negative and positive affective state, respectively, were recorded during basal and punished heroin self-administration and a novel dual stressor-induced reinstatement model to delineate affective profiles. In a separate cohort of conventional Sprague-Dawley rats, ex vivo electrophysiology in DRN 5-HT cells examined the impact of stress-induced reinstatement of heroin seeking on spontaneous inhibitory postsynaptic currents (sIPSCs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Activation of the DRN 5-HT system increased heroin consumption under basal and punished conditions but did not alter stress-induced reinstatement or affective measures. Although females showed higher active lever pressing and consumption of heroin intake during acquisition of self-administration, responses to DRN 5-HT activation did not differ by sex. Ex vivo recordings revealed elevated sIPSCs in DRN 5-HT neurons from post-reinstatement females, but not males, indicating increased inhibitory drive. Notably, chemogenetic viral expression was densest in the dorsal DRN (DRD), associated with anxiety-related behavior, whereas electrophysiological recordings targeted ventrolateral\/ventral DRN (DRVL\/DRV) regions linked to anxiolysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings demonstrate a role for the DRN 5-HT system in basal and punished heroin self-administration and a link between stress-induced heroin reinstatement and enhanced GABAergic inhibition of DRN 5-HT neurons in females. Serotonergic involvement in heroin consumption and sex differences in stress-driven heroin seeking patterns may reflect differential engagement of anatomically and functionally distinct DRN subdivisions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00213-026-07082-z","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T01:49:11Z","timestamp":1778636951000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Involvement of the dorsal raphe serotonin system in basal and punished heroin self-administration and stress-induced reinstatement in male and female rats"],"prefix":"10.1007","author":[{"given":"Claire","family":"Deckers","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Doretta","family":"McCully","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Meissler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynn G.","family":"Kirby","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"7082_CR1","doi-asserted-by":"publisher","first-page":"313","DOI":"10.3109\/00952990.2011.596982","volume":"37","author":"SE Back","year":"2011","unstructured":"Back SE, Payne RL, Wahlquist AH et al (2011) Comparative profiles of men and women with opioid dependence: results from a national multisite effectiveness trial. 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