Antidepressant effect of pramipexole in mice forced swimming test: A cross talk between dopamine receptor and NMDA/nitric oxide/cGMP pathway

⿢Pramipexole has the rapid antidepressant-like effect in mouse forced swimming test.⿢Dopamine D2 receptor antagonists prevent the rapid antidepressant- like effect of pramipexole.⿢Co-administration of sub-effective dose of pramipexole and NOS inhibitors or MK-801 exert antidepressant-like effect.⿢l-Arginine or NMDA prevent the rapid antidepressant-like effect of pramipexole.⿢Sildenafil prevent the rapid antidepressant-like effect of pramipexole.

Pramipexole is a dopamine D2 receptor agonist indicated for treating Parkinson disorder. This study was aimed to investigate the effect of pramipexole in forced swimming test (FST) in mice and the possible involvement of activation of D2 receptors and inhibition of N-methyl-d-aspartate (NMDA) receptors and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) on this effect. Intraperitoneal administration of pramipexole (1⿿3 mg/kg) reduced the immobility time in the FST similar to fluoxetine (20 mg/kg, i.p.). This effect of pramipexole (1 mg/kg, i.p.) was ceased when mice were pretreated with haloperidol (0.15 mg/kg, i.p,) and sulpiride (5 mg/kg, i.p) as D2 receptor antagonists, NMDA (75 mg/kg,i.p.), l-arginine (750 mg/kg, i.p., a substrate for nitric oxide synthase) or sildenafil (5 mg/kg, i.p., a phosphodiesterase 5 inhibitor). The administration of MK-801 (0.05 mg/kg, i.p., a NMDA receptor antagonist) l-NG-Nitro arginine methyl ester (l-NAME, 10 mg/kg, i.p., a non-specific nitric oxide synthase (NOS) inhibitor), 7-nitroindazole (30 mg/kg, i.p., a neuronal NOS inhibitor) and methylene blue (10 mg/kg, i.p.), an inhibitor of both NOS and soluble guanylyl cyclase (sGC) in combination with the sub-effective dose of pramipexole (0.3 mg/kg, i.p.) reduced the immobility. Altogether, our data suggest that the antidepressant-like effect of pramipexole is dependent on the activation of D2 receptor and inhibition of either NMDA receptors and/or NO-cGMP synthesis. These results contribute to the understanding of the mechanisms underlying the antidepressant-like effect of pramipexole and reinforce the role of D2 receptors, NMDA receptors and l-arginine-NO-GMP pathway in the antidepressant mechanism of this agent.

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