{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T11:31:19Z","timestamp":1791545479424,"version":"4.3.4"},"reference-count":126,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"National Science Centre","doi-asserted-by":"publisher","award":["2015\/17\/B\/NZ7\/03018"],"award-info":[{"award-number":["2015\/17\/B\/NZ7\/03018"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008725","name":"Maj Institute of Pharmacology, Polish Academy of Sciences","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100008725","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We investigated whether the functional involvement of \u03b11-adrenergic receptors (\u03b11-AR) in the effects induced by antidepressant drugs, desipramine, and milnacipran varies depending on the \u03b11-AR subtype. First, using a mouse line with triple knockout (KO) of genes encoding all three \u03b11-AR subtypes (ABD-KO) and autoradiographic analysis, we demonstrated that the inactivation of \u03b11-AR did not affect the density of other types of adrenergic receptors, \u03b12- and \u03b2-AR in the mouse brain. Subsequently, we utilized three mouse knockout lines with selective knockout of the gene encoding a single \u03b11-adrenergic receptor subtype (A-KO, B-KO, and D-KO). We analyzed the impact of these mutations on tissue levels of monoaminergic neurotransmitters in the hypothalamus (HY). Next, we assessed how a specific mutation affects the chronic effects of desipramine and milnacipran in the selected brain regions of male and female mice at various molecular levels: mRNA expression of genes encoding for \u03b11-AR subtypes, gene expression profiling, and phosphorylation of selected signaling proteins (ERK1\/2, Akt, GSK3\u03b2). The main finding is that the deletion of the \u03b11D subtype predominantly reduced the chronic effects of milnacipran at the examined transcriptomic and proteomic levels. The pattern of changes differed by gender. Our study revealed the functional diversity between \u03b11-AR subtypes in the molecular mechanisms of antidepressants\u2019 drug action.<\/jats:p>","DOI":"10.3390\/ijms262110488","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T17:02:01Z","timestamp":1761670921000},"page":"10488","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Differential Involvement of \u03b11-Adrenoceptor Subtypes in the Molecular Effects of Antidepressant Drugs"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7821-0206","authenticated-orcid":false,"given":"Irena","family":"Nalepa","sequence":"first","affiliation":[{"name":"Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6251-5021","authenticated-orcid":false,"given":"Katarzyna","family":"Chor\u0105zka","sequence":"additional","affiliation":[{"name":"Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3719-2889","authenticated-orcid":false,"given":"Grzegorz","family":"Kreiner","sequence":"additional","affiliation":[{"name":"Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0169-3916","authenticated-orcid":false,"given":"Agnieszka","family":"Zelek-Molik","sequence":"additional","affiliation":[{"name":"Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3925-3828","authenticated-orcid":false,"given":"Anna","family":"Haduch","sequence":"additional","affiliation":[{"name":"Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1226-1721","authenticated-orcid":false,"given":"W\u0142adys\u0142awa Anna","family":"Daniel","sequence":"additional","affiliation":[{"name":"Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8935-8591","authenticated-orcid":false,"given":"Piotr","family":"Chmielarz","sequence":"additional","affiliation":[{"name":"Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Maziarz","sequence":"additional","affiliation":[{"name":"Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6464-5620","authenticated-orcid":false,"given":"Justyna","family":"Ku\u015bmierczyk","sequence":"additional","affiliation":[{"name":"Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2758-3184","authenticated-orcid":false,"given":"Micha\u0142","family":"Wilczkowski","sequence":"additional","affiliation":[{"name":"Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1068-1028","authenticated-orcid":false,"given":"Adam","family":"Bielawski","sequence":"additional","affiliation":[{"name":"Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Kowalska","sequence":"additional","affiliation":[{"name":"Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1016\/S0006-3223(99)00140-7","article-title":"Role of Locus Coeruleus in Attention and Behavioral Flexibility","volume":"46","author":"Rajkowski","year":"1999","journal-title":"Biol. 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