To elucidate the ameliorative effect and underlying mechanisms of the 5-HT2A receptor inverse agonist LPM6690061 on pramipexole(PPX)-induced mania in mice with Parkinson's disease(PD),we first established a PD mouse model employing 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine(MPTP).A PD-associated mouse ma-nia model was subsequently induced through intraperitoneal injection of PPX.The mice were then subjected to treatment with 2.0,6.0,and 18.0 mg/kg LPM6690061.A suite of behavioral and neurobiological assays was em-ployed to assess the impact of LPM6690061.Dyskinesia in PD mice was evaluated using the rotarod and pole tests,while mood disorders in PD-manic mice were assessed through the tail suspension and forced swimming tests.Over-activity symptoms in PD-manic mice were measured via the open-field test,and spatial memory impairments were gauged using the Y-maze test.Neuroanatomical evaluations involved hematoxylin-eosin(HE)staining to detect cel-lular damage within the granule cells of the hippocampal dentate gyrus(DG).Western blotting was used to detect the expression of glycogen lyase kinase 3 β(GSK-3 β),phosphorylated GSK-3 β(P-GSK-3 β),serine/threonine ki-nase(Akt),phosphorylated Akt(P-Akt),extracellular regulating kinase(Erk),phosphorylated Erk(P-Erk),cy-clic-AMP response binding protein(CREB),phosphorylated CREB(P-CREB)in the mouse hippocampus.The findings suggest that the 5-HT2A receptor inverse agonist LPM6690061 mitigates the manic symptoms induced by pramipexole in PD mice.It accomplishes this by inhibiting the Akt/GSK-3 β signaling pathway,evidenced by de-creased expression of P-GSK-3 β and P-Akt proteins in the hippocampus.Concurrently,LPM6690061 enhances the Erk/CREB pathway,as indicated by increased expression of P-Erk and P-CREB proteins in the hippocampus.These alterations were accompanied by a reduction in neurons apoptosis,an improvement in spatial memory,and an attenuation of damage to the granule cells in the DG area of the hippocampus.
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