Additive interaction between scopolamine and nitric oxide agents on immobility in the forced swim test but not exploratory activity in the hole-board

Rationale The muscarinic cholinergic antagonist scopolamine has received an attention due to its unique antidepressant effects. However, the considerable adverse effects on nervous system limit the use of scopolamine as a psychiatric drug. Objective In order to overcome the limitations and increase the therapeutic effects of scopolamine, we decided to examine the effects of joint administration of sub-effective dose of scopolamine and the sub-effective dose of a nitric oxide (NO) precursor l-Arginine or a non-selective nitric oxide synthase (NOS) inhibitor l-NAME on depression- and anxiety-related behaviors in male NMRI mice. Methods To this aim, animal behavior was assessed in the forced swim test (FST) and hole-board apparatus. Results Scopolamine (0.05 mg/kg) significantly decreased immobility time in the FST, suggesting an antidepressant-like effect. Moreover, l-Arginine (50 mg/kg) produced an antidepressant-like response in the FST and decreased head-dip counts in the hole-board apparatus, indicating an anxiety-like effect. The same doses of scopolamine and l-Arginine decreased the locomotor activity in mice. Joint administration of sub-effective dose of scopolamine (0.01 mg/kg) with a low dose of l-Arginine (25 mg/kg) or l-NAME (1 mg/kg) induced a profound antidepressant-like effect in the FST. These drug combinations did not influence on anxiety-related behaviors. Meanwhile, l-NAME alone did not alter the performance of mice in the FST and hole-board. Isobolographic analysis revealed an additive effect for scopolamine and l-Arginine or l-NAME. Conclusion Data suggests that NO agents could positively impact the therapeutic profile of scopolamine, because they might be useful for inducing antidepressant-like effect associated to scopolamine.