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
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.
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BibTeX
@article{tome2026antidepressantlike,
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}},
author = {Angelo Tomé and Joana Real and Daniel Rial and António Silva and Francisco Gonçalves and Cristina Lemos and Ana Patrícia Simões and Henrique Silva and Tsvetan Serchov and Knut Biber and Paula Agostinho and Rodrigo Cunha},
journal = {Neuropharmacology},
year = {2026},
month = oct,
doi = {10.1016/j.neuropharm.2026.111056},
url = {https://hal.science/hal-05774536v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - 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
AU - Angelo Tomé
AU - Joana Real
AU - Daniel Rial
AU - António Silva
AU - Francisco Gonçalves
AU - Cristina Lemos
AU - Ana Patrícia Simões
AU - Henrique Silva
AU - Tsvetan Serchov
AU - Knut Biber
AU - Paula Agostinho
AU - Rodrigo Cunha
PY - 2026
DA - 2026/10/01
JO - Neuropharmacology
DO - 10.1016/j.neuropharm.2026.111056
UR - https://hal.science/hal-05774536v1
AB - 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.
SN - 0028-3908
SN - 1873-7064
ER -