Thesis (Ph.D)-Cairo University,2022.

Bibliography: p. 94-119.

Adenosinergic system dysfunction is implicated in the pathophysiology of multiple neuropsychiatric disorders including mania and bipolar disease. The established synergistic interaction between adenosine A2A (A2A) and dopamine (D2) receptors in the prefrontal cortex could highlight the idea of A2AR antagonism as a possible anti-manic strategy. Hence, the present study was performed to examine the effect of a selective A2AR blocker (SCH58261) on methylphenidate induced mania like behavior while investigating the underling mechanisms. Rats were injected with methylphenidate (5 mg/kg/day, i.p.) for three 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, A2AR antagonism reduced locomotor hyperactivity and risk-taking behavior along with decreased dopamine and glutamate levels. Meanwhile, SCH58261 restored N-methyl-D-aspartate receptor (NMDA) function, suppressed protein kinase C-alpha (PKC-α) expression, down-regulated β-Arrestin-2, up-regulated phosphorylated protein kinase B (pS473-Akt) and glycogen synthase kinase-3β (pS9-GSK-3β). Further, SCH58261 promoted synaptic plasticity markers through increasing brain derived neurotrophic factor (BDNF) level along with down-regulating growth-associated protein-43 (GAP-43) and synaptosomal associated protein-25 (SNAP-25). The A2A antagonist also reduced nuclear factor-kappa B p65 (NF-κBp65) and tumor necrosis factor-alpha (TNF-α) together with elevating interleukin-27 (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 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).