Role of nitric oxide in obsessive-compulsive behavior and its involvement in the anti-compulsive effect of paroxetine in mice

In view of the reports that nitric oxide modulates the neurotransmitters implicated in obsessive-compulsive disorder, patients with obsessive-compulsive disorder exhibit higher plasma nitrate levels, and drugs useful in obsessive-compulsive disorder influence nitric oxide, we hypothesized that nitric oxide may have some role in obsessive-compulsive behavior. We used marble-burying behavior of mice as the animal model of obsessive-compulsive disorder, and nitric oxide levels in brain homogenate were measured using amperometric nitric oxide-selective sensor method. Intraperitoneal administration of nitric oxide enhancers viz. nitric oxide precursor-l-arginine (800 mg/kg), nitric oxide donor-sodium nitroprusside (3 mg/kg) or phosphodiesterase type 5 inhibitor-sildenafil (3 mg/kg) significantly increased marble-burying behavior as well as brain nitrites levels, whereas treatment with 7-nitroindazole-neuronal nitric oxide synthase inhibitor (20-40 mg/kg, i.p.) or paroxetine-selective serotonin reuptake inhibitor (5-10 mg/kg, i.p.) dose dependently attenuated marble-burying behavior and nitrites levels in brain. Further, co-administration of sub-effective doses of 7-nitroindazole (10 mg/kg) and paroxetine (2.5 mg/kg) significantly attenuated marble-burying behavior. Moreover, pretreatment with l-arginine (400 mg/kg, i.p.), sodium nitroprusside (2.0 mg/kg, i.p.) or sildenafil (2.0 mg/kg, i.p.) significantly attenuated the inhibitory influence of 7-nitroindazole (40 mg/kg) or paroxetine (10 mg/kg) on marble-burying behavior as well as on brain nitrites levels. None of the above treatment had any significant influence on locomotor activity. In conclusion, obsessive compulsive behavior in mice appears related to nitric oxide in brain, and anti-compulsive effect of paroxetine appears to be related to decrease central levels of nitric oxide.