{
  "abstract": "BACKGROUND Many neuropsychiatric disorders involve dysregulation of the dopaminergic (DA) input to the forebrain. Of particular relevance are DA afferents from the midbrain ventral tegmental area (VTA). A key neuromodulatory influence onto DA VTA neurons arises from lateral hypothalamic area hypocretin/orexin (OX) neurons. Despite being a major input, the differential actions of OX peptides A and B on their receptors (OX 1 R and OX 2 R) in DA neurons is poorly understood. METHODS Using genetically engineered mice whose DA cells selectively lack OX input via Hcrtr1 (DA Ox1R-KO ) or Hcrtr2 (DA Ox2R-KO ), we assessed DA VTA neuron intrinsic excitability ex vivo , and evaluated behavioral phenotypes across socio-emotional and cognitive domains. RESULTS We discovered previously unrecognized effects of OX peptides on DA VTA cell response. While OXA enhanced DA VTA neuron firing via OX 1 R, OXB diminished firing via OX 2 R. Behaviorally, DA OX 1 R loss generated anxiety-like responding and context-dependent hyperactivity, while DA OX 2 R loss decreased sociability and compromised aversion-driven learning. Loss of either OX 1 R or OX 2 R in DA cells elicited impulsivity and compulsivity-like behavioral patterns. CONCLUSIONS We evidence distinct functions of OX 1 R vs OX 2 R signaling in modulating the intrinsic excitability of DA VTA neurons, and influencing DA-related behaviors. Our data implicate OX→DA signaling pathways in neuropsychiatric endophenotypes relevant to obsessive-compulsive, attention-deficit/hyperactivity, and autism spectrum disorders, and inform therapeutic strategies targeting orexin receptors.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland",
    "University of Lausanne",
    "Laboratory of Behavioral Genetics, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland",
    "Department of Biotechnology and Biosciences and NeuroMI (Milan Center of Neuroscience), University of Milano-Bicocca, Milano, Italy",
    "Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy",
    "CHUV and UNIL, Lausanne, Switzerland",
    "The University of Manchester, UK",
    "Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland. Electronic address: Anne.Vassalli@unil.ch"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Stamatina Tzanoulinou",
      "orcid": "0000-0002-6066-2810"
    },
    {
      "affs": [
        2
      ],
      "name": "Simone Astori",
      "orcid": "0000-0001-7698-8332"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Laura Clara Grandi",
      "orcid": "0000-0001-8174-5394"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Francesca Gullo",
      "orcid": "0000-0003-0496-7094"
    },
    {
      "affs": [
        0,
        5
      ],
      "name": "Richie Kalusivikako"
    },
    {
      "affs": [
        0,
        6
      ],
      "name": "Simran Rai"
    },
    {
      "affs": [
        0
      ],
      "name": "Galina Limorenko"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Mehdi Tafti",
      "orcid": "0000-0002-6997-3914"
    },
    {
      "affs": [
        3,
        1
      ],
      "name": "Andrea Becchetti",
      "orcid": "0000-0002-9297-0527"
    },
    {
      "affs": [
        7
      ],
      "name": "Anne Vassalli",
      "orcid": "0000-0002-5314-5620"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/eb75252srfv9h.bib",
  "cited_by": 5,
  "doi": "10.1016/j.biopsych.2026.05.022",
  "fulltext_url": null,
  "id": "eb75252srfv9h",
  "issns": [
    "0006-3223",
    "1873-2402"
  ],
  "landing_url": "https://doi.org/10.1016/j.biopsych.2026.05.022",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2805|Sleep and Wakefulness Research"
    ]
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  "openalex": "W4407604956",
  "pdf_url": null,
  "pmcid": null,
  "pmid": "42320783",
  "published": "2026-06-19",
  "publisher": "Elsevier BV",
  "ris": "https://research.draconitic.com/paper/eb75252srfv9h.ris",
  "sources": [
    {
      "first_seen": "2026-11-11T13:20:32Z",
      "native_id": "W4407604956",
      "source": "openalex",
      "url": "https://doi.org/10.1016/j.biopsych.2026.05.022"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2805|Sleep and Wakefulness Research",
      "subfield": "neuroscience"
    }
  ],
  "title": "Divergent Modulation of Dopaminergic Neurons by Hypocretin/Orexin Receptors 1 and 2 Shapes Dopaminergic Cell Activity and Socioemotional Behavior",
  "title_text": "Divergent Modulation of Dopaminergic Neurons by Hypocretin/Orexin Receptors 1 and 2 Shapes Dopaminergic Cell Activity and Socioemotional Behavior",
  "type": "peer-reviewed",
  "updated_at": "2026-11-13T13:21:09Z",
  "url": "https://research.draconitic.com/paper/eb75252srfv9h",
  "venue": "Biological Psychiatry",
  "versions": []
}