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Here, we aimed to characterize the functional-morphological changes of the main orexigenic and anorexigenic hypothalamic peptidergic systems in the rotenone model of PD in male rats. We also tested their response to benserazide\/levodopa (B\/L) anti-PD therapy alone or in combination with antidepressant (fluoxetine) medication. In the model, anhedonia and compromised motor coordination were observed in sucrose preference and rotarod tests respectively, with an acceptable therapeutic response. RNAscope in situ hybridization, combined with immunofluorescence, revealed that rotenone did not cause significant peptidergic neuron loss in the hypothalamus but reduced the expression of hypocretin and proopiomelanocortin mRNAs, in line with reduced orexin-1 and \u03b1-melanocyte-stimulating hormone immunoreactivities. The expression of neuropeptide y and cocaine- and amphetamine-regulated transcript was downregulated only at the mRNA level. B\/L alone or in combination with fluoxetine failed to reverse these functional-morphological changes. Our findings suggest complex functional alterations in both orexinergic and anorexigenic peptidergic systems in the rat model of PD that are not reversed by anti-PD and antidepressant administration.<\/jats:p>","DOI":"10.1038\/s41598-026-51774-7","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T19:55:20Z","timestamp":1777924520000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Hypothalamic orexigenic and anorexigenic neuropeptides in the rotenone model of Parkinson\u2019s disease"],"prefix":"10.1038","volume":"16","author":[{"given":"Zsombor","family":"M\u00e1rton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bence","family":"Pytel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e1vid","family":"Kov\u00e1cs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1t\u00e9","family":"Szab\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zs\u00f3fia","family":"Havasi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gergely","family":"Berta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f3zsef","family":"Farkas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e1szl\u00f3 \u00c1kos","family":"Kov\u00e1cs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00f3ra","family":"F\u00fcredi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikt\u00f3ria","family":"Kormos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2830-2732","authenticated-orcid":false,"given":"Bal\u00e1zs","family":"Gaszner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"51774_CR1","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1136\/jnnp.2007.131045","volume":"79","author":"J Jankovic","year":"2008","unstructured":"Jankovic, J. 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