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Adenosine A2A receptor blockade reverts hippocampal stress-induced deficits and restores corticosterone circadian oscillation

Abstract

Maternal separation (MS) is an early life stress model that induces permanent changes in the central nervous system, impairing hippocampal long-term potentiation (LTP) and spatial working memory. There are compelling evidences for a role of hippocampal adenosine A2A receptors in stress-induced modifications related to cognition, thus opening a potential window for therapeutic intervention. Here, we submitted rats to MS and evaluated the long-lasting molecular, electrophysiological and behavioral impairments in adulthood. We then assessed the therapeutic potential of KW6002, a blocker of A2A receptors, in stress-impaired animals. We report that the blockade of A2A receptors was efficient in reverting the behavior, electrophysiological and morphological impairments induced by MS. In addition, this effect is associated with restoration of the hypothalamic-pituitary-adrenal axis (HPA-axis) activity, as both the plasma corticosterone levels and hippocampal glucocorticoid receptor expression pattern returned to physiological-like status after the treatment. These results reveal the involvement of A2A receptors in the stress-associated impairments and directly in the stress response system by showing that the dysfunction of the HPA-axis as well as the long-lasting synaptic and behavioral effects of MS can be reverted by targeting adenosine A2A receptors. These findings provide a novel evidence for the use of adenosine A2A receptor antagonists as potential therapy against psychopathologies.

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Acknowledgements

We acknowledge Alexandre de Mendonça, David Blum and Rodrigo Cunha for helpful discussions. VLB is thankful to João Baião and Carla Batalha for technical assistance. VLB has been awarded a PhD fellowship from Fundação para a Ciência e Tecnologia (BD/63041/2009). LVL is funded by Fundação para a Ciência e Tecnologia (PTDC/SAU-NEU/099853/2008) and by EU programme Égide-Pessoa. YB and CEM were funded by the Ministry for Education and Research (BMBF, Grant number 01EW0911) in the frame of ERA-NET NEURON.

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Batalha, V., Pego, J., Fontinha, B. et al. Adenosine A2A receptor blockade reverts hippocampal stress-induced deficits and restores corticosterone circadian oscillation. Mol Psychiatry 18, 320–331 (2013). https://doi.org/10.1038/mp.2012.8

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Keywords

  • adenosine A2A receptors
  • corticosterone
  • hippocampus
  • HPA-axis
  • maternal separation
  • stress

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