{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T01:51:23Z","timestamp":1780451483937,"version":"3.54.1"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T00:00:00Z","timestamp":1747353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p> Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) exhibit a significant degree of comorbidity. Nevertheless, the specific effects and underlying mechanisms by which alcohol, as a risk factor, contributes to the development of PTSD-ike phenotypes remain poorly understood. Both chronic alcohol consumption and exposure to traumatic stress can lead to synaptic damage in the hippocampus, potentially serving as a neurobiological basis for the exacerbation of PTSD induced by alcohol.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, an animal model was established by allowing mice to voluntarily consume alcohol for 2 weeks, followed by exposure to a single prolonged stress combined with foot shock (SPS&amp;amp;FS). Subsequently, the mice received an intraperitoneal injection of rolipram (1 mg\/kg), and behavioral, biochemical, and morphological analyses were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The findings revealed that individuals with early alcohol exposure exhibited more pronounced deficits in fear extinction during the fear extinction task (FET) and displayed higher levels of anxiety-like behavior in both the open field test (OFT) and the elevated plus maze test (EPM). Activation of cAMP-PKA signaling enhanced the downregulation of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB), upregulated the expression of PSD95, synaptophysin, AMPA, and NMDA receptor subtypes, and reversed the impairment of CA1 synaptic function and dendritic structure in the hippocampus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Activation of the cAMP-PKA pathway facilitated fear extinction in PTSD mice with early alcohol exposure, alleviated anxiety-like behavior, attenuated symptoms of AUD following ethanol relapses. These findings suggest that modulating hippocampal synaptic plasticity by activating the cAMP-PKA pathway may represent a promising therapeutic approach for attenuating alcohol-exacerbated PTSD-like behaviors.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1592187","type":"journal-article","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T05:21:01Z","timestamp":1747372861000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["The regulation and mechanism of the cAMP-PKA pathway on PTSD-like behaviors exacerbated by alcohol exposure"],"prefix":"10.3389","volume":"16","author":[{"given":"Shuang","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangjiao","family":"Zong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanting","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,16]]},"reference":[{"key":"B1","first-page":"265","article-title":"Ethanol disrupts reactivated contextual conditioned fear memory: behavioral and histological perspectives","volume":"13","author":"Alijan-Pour","year":"2012","journal-title":"Cell J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2035","DOI":"10.1007\/s00213-016-4257-2","article-title":"Forced swim stress increases ethanol consumption in C57BL\/6J mice with a history of chronic intermittent ethanol exposure","volume":"233","author":"Anderson","year":"2016","journal-title":"Psychopharmacol. 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