Adenosine A2A Receptor Blockade Ameliorates Mania Like Symptoms in Rats: Signaling to PKC-α and Akt/GSK-3β/β-Catenin

Abstract

Adenosinergic system dysfunction is implicated in the pathophysiology of multiple neuropsychiatric disorders including mania and bipolar diseases. The established synergistic interaction between A2A and D2 receptors in the prefrontal cortex could highlight the idea of A2A receptor antagonism as a possible anti-manic strategy. Hence, the present study was performed to examine the effect of a selective adenosine A2A 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 A2AR 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 A2A 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 A2AR inhibition, could introduce adenosine A2AR as a possible therapeutic target for treatment of mania-like behavior. This notion is supported by the ability of the A2AR antagonist (SCH58261) to produce comparable results to those observed with the standard anti-manic drug (Lithium).