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Adenosine A<jats:sub>2A<\/jats:sub> receptors (A<jats:sub>2A<\/jats:sub>R) control emotional memory and fear conditioning, but it is not known if they affect the consolidation and generalization of fear, which was now investigated. We now report that A<jats:sub>2A<\/jats:sub>R blockade through systemic administration of the A<jats:sub>2A<\/jats:sub>R antagonist SCH58261 immediately after contextual fear conditioning (within the consolidation window), accelerated fear generalization. Conversely, A<jats:sub>2A<\/jats:sub>R activation with CGS21680 decreased fear generalization. Ex vivo electrophysiological recordings of field excitatory post-synaptic potentials (fEPSPs) in CA3-CA1 synapses and of population spikes in the lateral amygdala (LA), showed that the effect of SCH58261 is associated with a reversion of fear conditioning-induced decrease of long-term potentiation (LTP) in the dorsal hippocampus (DH) and with increased amplitude of LA LTP in conditioned animals. These data suggest that A<jats:sub>2A<\/jats:sub>R are engaged during contextual fear consolidation, controlling long-term potentiation mechanisms in both DH and LA during fear consolidation, impacting on fear generalization; this supports targeting A<jats:sub>2A<\/jats:sub>R during fear consolidation to control aberrant fear processing in PTSD and other fear-related disorders.<\/jats:p>","DOI":"10.1038\/s41398-023-02613-0","type":"journal-article","created":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T10:02:34Z","timestamp":1697104954000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Adenosine A2A receptors control generalization of contextual fear in rats"],"prefix":"10.1038","volume":"13","author":[{"given":"Ana P.","family":"Sim\u00f5es","sequence":"first","affiliation":[]},{"given":"Marina A. 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