Adenosine A_2A Receptor Blockade Ameliorates Mania Like Symptoms in Rats: Signaling to PKC-α and Akt/GSK-3β/β-Catenin

Adenosinergic system dysfunction is implicated in the pathophysiology of multiple neuropsychiatric disorders including mania and bipolar diseases. The established synergistic interaction between A_2A and D₂ receptors in the prefrontal cortex could highlight the idea of A_2A receptor antagonism as a possible anti-manic strategy. Hence, the present study was performed to examine the effect of a selective adenosine A_2A receptor blocker (SCH58261) on methylphenidate-induced mania-like behavior while investigating the underlying mechanisms. Rats were injected with methylphenidate (5 mg/kg/day, i.p.) for 3 weeks with or without administration of either SCH58261 (0.01 mg/kg/day, i.p.) or lithium (150 mg/kg/day, i.p.) starting from day 9. In the diseased rats, adenosine A_2AR antagonism reduced locomotor hyperactivity and risk-taking behavior along with decreased dopamine and glutamate levels. Meanwhile, SCH58261 restored NMDA receptor function, suppressed PKC-α expression, down-regulated β-Arrestin-2, up-regulated pS473-Akt and pS9-GSK-3β. Further, SCH58261 promoted synaptic plasticity markers through increasing BDNF levels along with down-regulating GAP-43 and SNAP-25. The A_2A antagonist also reduced NF-κBp65 and TNF-α together with elevating IL-27 level giving an anti-inflammatory effect. In conclusion, suppression of PKC-α and modulation of Akt/GSK-3β/β-catenin axis through A_2AR inhibition, could introduce adenosine A_2AR as a possible therapeutic target for treatment of mania-like behavior. This notion is supported by the ability of the A_2AR antagonist (SCH58261) to produce comparable results to those observed with the standard anti-manic drug (Lithium).