{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:55:19Z","timestamp":1790794519538,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100005892","name":"China Academy of Chinese Medical Sciences","doi-asserted-by":"publisher","award":["CI2025C002LH"],"award-info":[{"award-number":["CI2025C002LH"]}],"id":[{"id":"10.13039\/501100005892","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Morphine\u2010associated contextual reward learning promotes maladaptive drug\u2013context associations during opioid exposure. Hederagenin (HE), a bioactive compound from traditional Chinese medicine, has neuroprotective potential, but its role in contextual reward learning remains unclear. Here, we investigated the effects of HE on morphine\u2010induced conditioned place preference (CPP) acquisition and explored its target, downstream signaling, and brain\u2010delivery strategy. HE attenuated morphine CPP acquisition in both sexes and reduced established CPP expression. Chemical proteomics identified the GABAA receptor \u03b11 subunit (GABAA1, encoded by GABRA1) as a prioritized HE\u2010associated target, supported by competitive pull\u2010down, non\u2010permeabilized HE\u2010biotin labeling, microscale thermophoresis, cellular thermal shift assay, and molecular docking. Mechanistically, HE reduced c\u2010Fos activation in ventral tegmental area (VTA) TH\u2010positive dopaminergic neurons, attenuated reward\u2010context\u2010associated VTA calcium responses, suppressed intracellular Ca\n                    <jats:sup>2<\/jats:sup>\n                    <jats:sup>+<\/jats:sup>\n                    elevation in SH\u2010SY5Y cells, and reduced VTA CaMKII, PKA, and CREB phosphorylation. Animal\u2010level analyses linked CPP scores to compartment\u2010selective VTA calcium responses and p\u2010CREB\/CREB ratios, whereas TH\n                    <jats:sup>+<\/jats:sup>\n                    \/c\u2010Fos\n                    <jats:sup>+<\/jats:sup>\n                    associations varied by treatment. Compared with non\u2010targeted liposomes, RVG29\u2010modified HE\u2010loaded liposomes showed greater brain\u2010 and VTA\u2010associated distribution and suppressed established CPP after a single administration. Together, these findings identify HE as a candidate modulator of morphine CPP through a GABAA1\u2010related VTA Ca\n                    <jats:sup>2<\/jats:sup>\n                    <jats:sup>+<\/jats:sup>\n                    \u2013CaMK\u2013cAMP\u2013CREB mechanism and support RVG29 liposomes as an exploratory delivery strategy.\n                  <\/jats:p>","DOI":"10.1002\/advs.77820","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hederagenin Attenuates Morphine Addiction via GABAA1\u2010Mediated Modulation of Ca\n                    <sup>2<\/sup>\n                    <sup>+<\/sup>\n                    \u2013CaMK\u2013CREB Signaling in Ventral Tegmental Dopaminergic Neurons"],"prefix":"10.1002","author":[{"given":"Hongyang","family":"Jiang","sequence":"first","affiliation":[{"name":"State 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