{
  "abstract": "The action of different fast-acting antidepressant strategies, ranging from ketamine to deep brain stimulation, seems to involve an increased function of adenosine A 1 receptors (A 1 R). A 1 R are mostly located in excitatory synapses and trigger a general inhibition of brain function. Thus, we now resorted to mice overexpressing A 1 R in forebrain neurons (oeA1R) to test if and how synaptic A 1 R were selectively engaged to control mood. We first confirmed that oeA1R mice displayed an anxiolytic and resilient behavior profile with no evident alteration of working or reference memory, but with increased learning flexibility. Surprisingly, there was no modification of the ability of A 1 R agonists or antagonists (DPCPX) to control synaptic transmission or short-term plasticity in excitatory synapses of either prefrontal cortex or dorsal hippocampus of oeA1R compared to WT mice. Accordingly, the binding density of A 1 R was mostly increased outside synapses (200% increase) rather than in synaptic membranes (20% increase) of the cerebral cortex. Moreover, the increased number of extra-synaptic A 1 R were G-protein-coupled ( i.e. potentially ‘active’) based on the displacement binding curves of the A 1 R agonist CPA in cerebrocortical membranes. This prompts the correlative conclusion that the anxiolytic and antidepressive effects of increased A 1 R levels might involve extra-synaptic A 1 R rather increased A 1 R function in synapses, which does not align with prevailing models emphasizing synaptic mechanisms in antidepressant action and paves the way to develop more selective antidepressants targeting these extra-synaptic A 1 R.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "name": "Angelo Tomé"
    },
    {
      "name": "Joana Real"
    },
    {
      "name": "Daniel Rial"
    },
    {
      "name": "António Silva"
    },
    {
      "name": "Francisco Gonçalves"
    },
    {
      "name": "Cristina Lemos"
    },
    {
      "name": "Ana Patrícia Simões"
    },
    {
      "name": "Henrique Silva"
    },
    {
      "name": "Tsvetan Serchov"
    },
    {
      "name": "Knut Biber"
    },
    {
      "name": "Paula Agostinho"
    },
    {
      "name": "Rodrigo Cunha"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fy6njrthhqk2k.bib",
  "cited_by": 0,
  "doi": "10.1016/j.neuropharm.2026.111056",
  "fulltext_url": null,
  "id": "fy6njrthhqk2k",
  "issns": [
    "0028-3908",
    "1873-7064"
  ],
  "landing_url": "https://hal.science/hal-05774536v1",
  "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": [
    [
      "hal",
      "0.sdv"
    ],
    [
      "openalex",
      "1314|Adenosine and Purinergic Signaling"
    ]
  ],
  "openalex": "W7163004888",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-01",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/fy6njrthhqk2k.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:46Z",
      "native_id": "hal-05774536",
      "source": "hal",
      "url": "https://hal.science/hal-05774536v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:1314|Adenosine and Purinergic Signaling",
      "subfield": "physiology"
    }
  ],
  "title": "The antidepressant-like effect of adenosine A1 receptor over-expression in forebrain neurons does not involve an altered adenosine-mediated control of excitatory synaptic transmission",
  "title_text": "The antidepressant-like effect of adenosine A1 receptor over-expression in forebrain neurons does not involve an altered adenosine-mediated control of excitatory synaptic transmission",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:46Z",
  "url": "https://research.draconitic.com/paper/fy6njrthhqk2k",
  "venue": "Neuropharmacology",
  "versions": []
}