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The established synergistic interaction between A<jats:sub>2A<\/jats:sub> and D<jats:sub>2<\/jats:sub> receptors in the prefrontal cortex could highlight the idea of A<jats:sub>2A<\/jats:sub> receptor antagonism as a possible anti-manic strategy. Hence, the present study was performed to examine the effect of a selective adenosine A<jats:sub>2A<\/jats:sub> receptor blocker (SCH58261) on methylphenidate-induced mania-like behavior while investigating the underlying mechanisms. Rats were injected with methylphenidate (5\u00a0mg\/kg\/day, i.p.) for 3\u00a0weeks with or without administration of either SCH58261 (0.01\u00a0mg\/kg\/day, i.p.) or lithium (150\u00a0mg\/kg\/day, i.p.) starting from day 9. In the diseased rats, adenosine A<jats:sub>2A<\/jats:sub>R antagonism reduced locomotor hyperactivity and risk-taking behavior along with decreased dopamine and glutamate levels. Meanwhile, SCH58261 restored NMDA receptor function, suppressed PKC-\u03b1 expression, down-regulated \u03b2-Arrestin-2, up-regulated <jats:italic>p<\/jats:italic>S473-Akt and <jats:italic>p<\/jats:italic>S9-GSK-3\u03b2. Further, SCH58261 promoted synaptic plasticity markers through increasing BDNF levels along with down-regulating GAP-43 and SNAP-25. The A<jats:sub>2A<\/jats:sub> antagonist also reduced NF-\u03baBp65 and TNF-\u03b1 together with elevating IL-27 level giving an anti-inflammatory effect. In conclusion, suppression of PKC-\u03b1 and modulation of Akt\/GSK-3\u03b2\/\u03b2-catenin axis through A<jats:sub>2A<\/jats:sub>R inhibition, could introduce adenosine A<jats:sub>2A<\/jats:sub>R as a possible therapeutic target for treatment of mania-like behavior. This notion is supported by the ability of the A<jats:sub>2A<\/jats:sub>R antagonist (SCH58261) to produce comparable results to those observed with the standard anti-manic drug (Lithium).\n<\/jats:p>","DOI":"10.1007\/s12035-022-02977-2","type":"journal-article","created":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T10:02:52Z","timestamp":1660039372000},"page":"6397-6410","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Adenosine A2A Receptor Blockade Ameliorates Mania Like Symptoms in Rats: Signaling to PKC-\u03b1 and Akt\/GSK-3\u03b2\/\u03b2-Catenin"],"prefix":"10.1007","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3879-7022","authenticated-orcid":false,"given":"Heba Nasr","family":"Shalaby","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hala Fahmy","family":"Zaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Afaf Abd Almonim","family":"Ain-Shoka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reham Atef","family":"Mohammed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,8,9]]},"reference":[{"key":"2977_CR1","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1124\/pharmrev.121.000445","volume":"74","author":"APJACE IJzermanJacobsonM\u00fcller","year":"2022","unstructured":"IJzerman AP, Jacobson KA, M\u00fcller CE\u00a0et al (2022) International Union of Basic and Clinical Pharmacology. 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