Synergistic effect between quinpirole and L-NAME as well as sulpiride and L-arginine on the modulation of anxiety and memory processes in the 6-OHDA mouse model of Parkinson's disease: An isobologram analysis

We evaluated interactions between dopamine D2 receptor and nitric oxide (NO) actions on the regulation of anxiety and memory in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease (PD). A unilateral guide cannula was stereotaxically implanted over the right striatum. Elevated plus-maze test (EPM) test-retest protocol was employed to evaluate anxiety and memory in mice. The results revealed that injection of L-NAME (9 mg/kg) induced anxiolytic and amnesic effects, while L-arginine (9 mg/kg) produced anxiogenic and memory-improvement effects in the 6-OHDA mouse model of PD. Administration of sulpiride (20 mg/kg) induced anxiogenic and memory-improvement effects, whereas quinpirole (20 mg/kg) caused anxiolytic and amnesic effects in PD mice. Co-injection of sulpiride (5, 10, and 20 mg/kg) plus L-NAME (3 mg/kg) induced anxiolytic and amnesic effects. Co-injection of sulpiride (20 mg/kg) plus L-arginine (3 mg/kg) induced anxiogenic and memory-improvement effects. Co-administrations of quinpirole (20 mg/kg) and L-NAME (3 mg/kg) induced anxiolytic effect, but co-administration of quinpirole (20 mg/kg) plus L-arginine (3 mg/kg) caused anxiogenic and memory-improvement effects. The isobologram analysis revealed that there is a synergistic effect between sulpiride and L-arginine as well as quinpirole and L-NAME upon induction of anxiogenic and anxiolytic effects, respectively in PD mice. Our results suggested: (1) NO and dopamine D2 receptor mechanisms affect anxiety and memory in PD mice; (2) L-NAME reversed anxiogenic and memory-improvement effect induced by sulpiride; (3) Anxiolytic and amnesic effects induced by quinpirole reversed by L-arginine; (4) There is a synergistic effect between dopamine D2 receptor and NO systems on the modulation of anxiety and memory.

Anxiety; Dopamine D2 receptor; Isobologram; Memory; Nitric oxide (NO); Parkinson's disease (PD).