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Moreover, it increases central 5\u2010hydroxytryptamine (5\u2010HT)\/brain\u2010derived neurotrophic factor (BDNF) or cyclic AMP response element binding protein (CREB) levels, but the exact role of these targets in its effect is still ill\u2010explained. Therefore, the present study explored the role of 5\u2010HT in berberine\u2010induced antidepressant\u2010like activity and BDNF or CREB expression in the specific brain regions. Administration of berberine (2, 5, and 20\u00a0mg\/kg, i.p.) significantly reduced the duration of immobility of mice in the tail suspension test (TST) model without affecting locomotor activity, confirming its antidepressant\u2010like potential. Preinjection with the 5\u2010HT precursor, 5\u2010hydroxytryptophan (5\u2010HTP; 50 and 100\u00a0\u00b5g\/mouse, intracerebroventricular [i.c.v.]), and the selective serotonin reuptake inhibitor (SSRI), fluoxetine (5 and 10\u00a0mg\/kg, i.p.), enhanced the berberine\u2010induced antidepressant\u2010like effect, whereas it was reversed in mice pretreated with 5\u2010HT<jats:sub>1A<\/jats:sub> receptor agonist, 8\u2010hydroxy\u20102(\u2010dipropylamino)tetralinhydrobromide (8\u2010OH\u2010DPAT) (0.01 and 0.1\u00a0\u00b5g\/mouse, i.c.v.), or the 5\u2010HT<jats:sub>2A\/2C<\/jats:sub> receptor antagonist, mianserin (1, 1.5\u00a0\u00b5g\/mouse, i.c.v.). Furthermore, berberine\u2010induced antidepressant\u2010like effects were significantly reduced in mice with depleted central 5\u2010HT, achieved by preinjection of the serotonin depletor, <jats:italic>p<\/jats:italic>\u2010chlorophenylalanine (<jats:italic>p<\/jats:italic>\u2010CPA; 300\u00a0mg\/kg, i.p.\u00a0\u00d7\u00a03 days). Additionally, berberine (20\u00a0mg\/kg, i.p.) treatment significantly elevated BDNF expression in the whole brain, prefrontal cortex (PFC), and hippocampus and increased CREB expression in the whole brain and hippocampus only. Notably, berberine\u2010induced elevated BDNF expression in the whole brain and hippocampus was further enhanced in mice pretreated with 5\u2010HTP, fluoxetine, or 8\u2010OH\u2010DPAT, whereas mianserin or <jats:italic>p<\/jats:italic>\u2010CPA reversed it. However, 5\u2010HTP enhanced and fluoxetine or 8\u2010OH\u2010DPAT did not alter, whereas mianserin or <jats:italic>p<\/jats:italic>\u2010CPA reversed the berberine\u2010induced heightened BDNF expression in the PFC. On the other hand, berberine significantly increased CREB expression in the whole brain, which was further potentiated in mice pretreated with 5\u2010HTP, fluoxetine, 8\u2010OH\u2010DPAT, or mianserin, whereas it was reversed by <jats:italic>p<\/jats:italic>\u2010CPA. However, berberine\u2010induced heightened CREB expression in the hippocampus was enhanced only in mice pretreated with 5\u2010HTP and attenuated by preinjection of mianserin or <jats:italic>p<\/jats:italic>\u2010CPA. These findings suggest that serotonergic transmission modulates the antidepressant\u2010like activity and the BDNF\/CREB alterations induced by berberine, likely through a mechanism mediated by 5\u2010HT<jats:sub>1A<\/jats:sub> and 5\u2010HT<jats:sub>2A\/2C<\/jats:sub> receptors. This study underscores the role of serotonergic transmission in the effects induced by berberine.<\/jats:p>","DOI":"10.1002\/syn.70028","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T10:20:38Z","timestamp":1756462838000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Berberine\u2010Induced Behavioral Effects on Tail Suspension Test, BDNF, and CREB Levels in the Prefrontal Cortex, Hippocampus, and Amygdala: Modulation by Central Serotonergic Transmission"],"prefix":"10.1002","volume":"79","author":[{"given":"Venu Anand Das","family":"Vaishnav","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Pharmacology Division, Neuropharmacology Lab Guru Ghasidas Vishwavidyalaya (A Central University)  Bilaspur Chhattisgarh India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richa","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmacology Division, Neuropharmacology Lab Guru Ghasidas Vishwavidyalaya (A Central University)  Bilaspur Chhattisgarh India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vaibhav","family":"Maturkar","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmacology Division, Neuropharmacology Lab Guru Ghasidas Vishwavidyalaya (A Central University)  Bilaspur Chhattisgarh India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chhatrapal","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmacology Division, Neuropharmacology Lab Guru Ghasidas Vishwavidyalaya (A Central University)  Bilaspur Chhattisgarh India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7230-2604","authenticated-orcid":false,"given":"Nishant Sudhir","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmacology Division, Neuropharmacology Lab Guru Ghasidas Vishwavidyalaya (A Central University)  Bilaspur Chhattisgarh India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0924-977X(00)00118-8"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-013-0071-0"},{"issue":"2","key":"e_1_2_9_4_1","first-page":"94","article-title":"Berberine: Therapeutic Potential of an Alkaloid Found in Several Medicinal Plants","volume":"2","author":"Birdsall T. 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