{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:12:17Z","timestamp":1792512737482,"version":"4.5.0"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"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. Behav. Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Dopamine system dysfunction is closely associated with nervous system diseases such as Parkinson\u2019s disease and psychiatric disorder. Current research is limited to the individual application of dopamine D1 and D2 receptor-related agents, and the systematic effects of combined dopamine D1\/D2 receptor inhibition on neural function remain unclear. In this study, we aimed to investigate the dose-dependent effects of co-DR1\/2I (combined administration of dopamine receptor 1 inhibitor SCH39166 and dopamine receptor 2 inhibitor raclopride) on oxidative stress, learning, memory, emotion, and motor function in the substantia nigra, striatum, and hippocampus of mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>After administering varying doses of co-DR1\/2I through gastric tubes to male C57BL\/6 mice, we used enzyme-linked immunosorbent assay to measure monoamine oxidase B (MAO-B), reactive oxygen species (ROS), and superoxide dismutase (SOD) activity. Behavioral changes were assessed, using open field, rotarod, and water maze tests. Tyrosine hydroxylase positive neurons were labeled with immunofluorescence, and tyrosine hydroxylase levels were detected by Western blot (WB) assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Low-dose co-DR1\/2I significantly increased MAO-B and ROS levels (<jats:italic>p<\/jats:italic> &amp;lt; 0.01) and decreased SOD activity (<jats:italic>p<\/jats:italic> &amp;lt; 0.01) in the substantia nigra, striatum, and hippocampus. MAO-B activity positively correlated with ROS (<jats:italic>r<\/jats:italic> = 0.916, <jats:italic>p<\/jats:italic> &amp;lt; 0.001) and negatively correlated with SOD (<jats:italic>r<\/jats:italic> = \u22120.685, <jats:italic>p<\/jats:italic> &amp;lt; 0.001), whereas ROS negatively correlated with SOD (<jats:italic>r<\/jats:italic> = \u22120.661, <jats:italic>p<\/jats:italic> &amp;lt; 0.001) in co-DR1\/2I-treated mice. The medium- and high-dose groups exhibited spatial memory impairment (longer escape latency, <jats:italic>p<\/jats:italic> &amp;lt; 0.05) in the water maze and more anxiety-like behavior (reduced central zone time, <jats:italic>p<\/jats:italic> &amp;lt; 0.01) in the open field test; however, no abnormalities in motor coordination were observed in the rotarod test (<jats:italic>p<\/jats:italic> &amp;gt; 0.05). Immunofluorescence and WB confirmed a reduction in the dopaminergic neuron count after co-DR1\/2I.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This is the first study to demonstrate that co-DR1\/2I triggers cognitive and emotional dysfunction by exacerbating oxidative stress and dopaminergic neuronal damage, thereby advancing our understanding of the neurotoxic mechanisms of dopamine receptor antagonists. Future studies are needed to explore targeted antioxidant therapies and receptor-selective modulation strategies to reduce the side effects.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnbeh.2025.1621017","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T05:26:26Z","timestamp":1754285186000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Combined inhibition of dopamine D1\/D2 receptors induces cognitive and emotional dysfunction through oxidative stress and dopaminergic neuron damage"],"prefix":"10.3389","volume":"19","author":[{"given":"Xue","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya Ru","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke Ke","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin Xin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin Xing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan Yi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"107402","DOI":"10.1016\/j.ntt.2024.107402","article-title":"Bisphenol F-induced precocious genesis of aggressive neurobehavioral response is associated with heightened monoamine oxidase activity and neurodegeneration in zebrafish brain.","volume":"106","author":"Bhoi","year":"2024","journal-title":"Neurotoxicol. Teratol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1783","DOI":"10.1038\/s41593-024-01694-4","article-title":"Striatal projection neurons coexpressing dopamine D1 and D2 receptors modulate the motor function of D1- and D2-SPNs.","volume":"27","author":"Bonnavion","year":"2024","journal-title":"Nat. Neurosci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1523\/JNEUROSCI.4576-09.2010","article-title":"Restricting dopaminergic signaling to either dorsolateral or medial striatum facilitates cognition.","volume":"30","author":"Darvas","year":"2010","journal-title":"J. Neurosci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"101263","DOI":"10.1016\/j.arr.2021.101263","article-title":"Oxidative stress and regulated cell death in Parkinson\u2019s disease.","volume":"67","author":"Dion\u00edsio","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"B5","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1146\/annurev-neuro-061010-113641","article-title":"Modulation of striatal projection systems by dopamine.","volume":"34","author":"Gerfen","year":"2011","journal-title":"Annu. Rev. Neurosci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1038\/s41586-025-08957-5","article-title":"Dopamine D1-D2 signalling in hippocampus arbitrates approach and avoidance.","volume":"643","author":"Godino","year":"2025","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1038\/nrn.2016.57","article-title":"Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression.","volume":"17","author":"Grace","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.biopsych.2016.07.014","article-title":"The role of genes, stress, and dopamine in the development of schizophrenia.","volume":"81","author":"Howes","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"B9","doi-asserted-by":"publisher","first-page":"100212","DOI":"10.1016\/j.prdoa.2023.100212","article-title":"Dopamine agonists in Parkinson\u2019s disease: Impact of D1-like or D2-like dopamine receptor subtype selectivity and avenues for future treatment.","volume":"9","author":"Isaacson","year":"2023","journal-title":"Clin. Park. Relat. Disord."},{"key":"B10","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1007\/s00401-024-02712-2","article-title":"Characterization of monoamine oxidase-B (MAO-B) as a biomarker of reactive astrogliosis in Alzheimer\u2019s disease and related dementias.","volume":"147","author":"Jaisa-Aad","year":"2024","journal-title":"Acta Neuropathol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.2174\/1570159X20666220915091022","article-title":"Advances in the therapeutic use of non-ergot dopamine agonists in the treatment of motor and non-motor symptoms of Parkinson\u2019s disease.","volume":"21","author":"Jing","year":"2023","journal-title":"Curr. Neuropharmacol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1002\/med.21923","article-title":"Recent advances in dopamine D(2) receptor ligands in the treatment of neuropsychiatric disorders.","volume":"43","author":"Juza","year":"2023","journal-title":"Med. Res. Rev."},{"key":"B13","doi-asserted-by":"publisher","first-page":"107704","DOI":"10.1016\/j.neuropharm.2019.107704","article-title":"Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology.","volume":"172","author":"Kaar","year":"2020","journal-title":"Neuropharmacology"},{"key":"B14","doi-asserted-by":"publisher","first-page":"515","DOI":"10.3390\/toxins15090515","article-title":"Endocrine effect of some mycotoxins on humans: A clinical review of the ways to mitigate the action of mycotoxins.","volume":"15","author":"Ko\u015bcielecka","year":"2023","journal-title":"Toxins (Basel)"},{"key":"B15","doi-asserted-by":"publisher","first-page":"24","DOI":"10.3390\/toxins17010024","article-title":"Neurotoxicological effects of some mycotoxins on humans health and methods of neuroprotection.","volume":"17","author":"Ku\u00e6-Szymanek","year":"2025","journal-title":"Toxins (Basel)"},{"key":"B16","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1385\/MN:30:1:077","article-title":"Perspectives on MAO-B in aging and neurological disease: Where do we go from here?\u201d.","volume":"30","author":"Kumar","year":"2004","journal-title":"Mol. Neurobiol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.cca.2021.08.009","article-title":"Dopamine in Parkinson\u2019s disease.","volume":"522","author":"Latif","year":"2021","journal-title":"Clin. Chim. Acta"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1292044","DOI":"10.3389\/fphys.2023.1292044","article-title":"Editorial: Oxidative stress and distinct cell death.","volume":"14","author":"Liu","year":"2023","journal-title":"Front. Physiol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1007\/BF00428152","article-title":"Antiemetic specificity of dopamine antagonists.","volume":"78","author":"Niemegeers","year":"1982","journal-title":"Psychopharmacology (Berl)"},{"key":"B20","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1177\/1179573517726335","article-title":"Abnormalities of dopamine D(3) receptor signaling in the diseased brain.","volume":"9","author":"Prieto","year":"2017","journal-title":"J. Cent. Nerv. Syst. Dis."},{"key":"B21","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1586\/14737175.2015.1038244","article-title":"Parkinson\u2019s disease: A review of non-motor symptoms.","volume":"15","author":"Rana","year":"2015","journal-title":"Expert Rev. Neurother."},{"key":"B22","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1134\/S1607672920030084","article-title":"Antagonists D1 and D2 of dopamine receptors determine different mechanisms of neuroprotective action in the frog vestibular.","volume":"492","author":"Ryzhova","year":"2020","journal-title":"Dokl. Biochem. Biophys."},{"key":"B23","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.etp.2011.11.003","article-title":"Involvement of monoamine oxidase-B in the acute neurotoxicity of MPTP in embryonic and newborn mice.","volume":"65","author":"Sai","year":"2013","journal-title":"Exp. Toxicol. Pathol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/s1353-8020(02)00014-7","article-title":"Is there a connection between estrogen and Parkinson\u2019s disease?\u201d.","volume":"8","author":"Shulman","year":"2002","journal-title":"Parkinsonism Relat. Disord."},{"key":"B25","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1002\/art.42697","article-title":"Oxidative stress by the mitochondrial monoamine oxidase B mediates calcium pyrophosphate crystal-induced arthritis.","volume":"76","author":"Venegas","year":"2024","journal-title":"Arthritis Rheumatol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"105542","DOI":"10.1016\/j.phrs.2021.105542","article-title":"The receptor hypothesis and the pathogenesis of depression: Genetic bases and biological correlates.","volume":"167","author":"Wang","year":"2021","journal-title":"Pharmacol. Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1007\/s00702-023-02647-0","article-title":"Role of dopamine agonists in Parkinson\u2019s disease therapy.","volume":"130","author":"Woitalla","year":"2023","journal-title":"J. Neural Transm."},{"key":"B28","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.neuro.2012.09.006","article-title":"Neurotoxic potential of iron oxide nanoparticles in the rat brain striatum and hippocampus.","volume":"34","author":"Wu","year":"2013","journal-title":"Neurotoxicology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"331","DOI":"10.13461\/j.cnki.cja.002971","article-title":"FMC: A dopamine 1 receptor inhibitor derived from Fusarium.","volume":"5","author":"Zhou","year":"2001","journal-title":"Chinese J. Antibiot."}],"container-title":["Frontiers in Behavioral Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnbeh.2025.1621017\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T05:26:28Z","timestamp":1754285188000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnbeh.2025.1621017\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,4]]},"references-count":29,"alternative-id":["10.3389\/fnbeh.2025.1621017"],"URL":"https:\/\/doi.org\/10.3389\/fnbeh.2025.1621017","relation":{},"ISSN":["1662-5153"],"issn-type":[{"value":"1662-5153","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,4]]},"article-number":"1621017"}}