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This interplay is of great interest since it holds promise as a target for preventing stress-related brain disorders, e.g., major depression. Our group has previously observed that prefrontal serotonin transporter (5-HTT) binding, imaged with positron emission tomography (PET), is positively associated with the cortisol awakening response (CAR), an index of HPA axis stress hormone dynamics. The aim of this cross-sectional study was to replicate the previous finding in a larger independent group of healthy individuals.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Molecular imaging and cortisol data were available for 90 healthy individuals. Prefrontal 5-HTT binding was imaged with [<jats:sup>11<\/jats:sup>C]DASB brain PET. Non-displaceable 5-HTT binding potential (BP<jats:sub>ND<\/jats:sub>) was quantified using the Multilinear Reference Tissue Model 2 (MRTM2) with cerebellum as the reference region. CAR was based on five serial salivary cortisol samples within the first hour upon awakening. The association between CAR and prefrontal 5-HTT BP<jats:sub>ND<\/jats:sub> was evaluated using a multiple linear regression model adjusted for age and sex. Further, we tested for sex differences in the association. Finally, an exploratory analysis of the association, was performed in 8 additional brain regions.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>We observed no statistically significant association between 5-HTT binding and CAR corrected for age and sex in the prefrontal cortex (\u03b2 = -0.28, p = 0.26). We saw no interaction with sex on the association (p = 0.99).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>We could <jats:italic>not<\/jats:italic> confirm a positive association between CAR and prefrontal 5-HTT BP<jats:sub>ND<\/jats:sub> in this independent dataset. Also, sex differences in the association were not apparent. Our data do not exclude that the serotonin transporter system is involved in the regulation of stress responses in at-risk or manifest depressed states.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0290663","type":"journal-article","created":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T17:40:10Z","timestamp":1693503610000},"page":"e0290663","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Is serotonin transporter brain binding associated with the cortisol awakening response? An independent non-replication"],"prefix":"10.1371","volume":"18","author":[{"given":"Juliane","family":"Conradi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonas","family":"E. 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Erritzoe","year":"2020","journal-title":"Neuropsychopharmacology"},{"key":"pone.0290663.ref036","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.euroneuro.2023.01.006","article-title":"In vivo serotonin transporter and 1A receptor binding potential and ecological momentary assessment (EMA) of stress in major depression and suicidal behavior","volume":"70","author":"EA Bartlett","year":"2023","journal-title":"Eur Neuropsychopharmacol"},{"issue":"9","key":"pone.0290663.ref037","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1016\/j.biopsych.2008.10.035","article-title":"Suppressed neuroendocrine stress response in depressed women on job-stress-related long-term sick leave: a stable marker potentially suggestive of preexisting vulnerability","volume":"65","author":"K Wahlberg","year":"2009","journal-title":"Biol Psychiatry"},{"key":"pone.0290663.ref038","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.physbeh.2016.11.014","article-title":"A users 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