The aim of this study was to characterize the behavioral effect of modulators of NO synthesis in the mouse marble-burying test. We found that the non-selective NOS inhibitor 7-nitroindazole (7-NI) as well as the more selective neuronal and inducible NOS inhibitor 1-(2-trifluoromethylphenyl)imidazole (TRIM) decreased the number of marbles buried. Treatment with NO precursor l-arginine alone (500mg/kg) had no effect in this paradigm, but counteracted the effects of paroxetine (10mg/kg) and citalopram (10mg/kg). Moreover, agmatine (20 and 50mg/kg i.p), a molecule related to l-arginine metabolism, inhibited the marble-burying behavior. This effect of agmatine was not related to inhibition of NO synthesis as the drug did not decrease the nitrate and nitrite level in the brain tissue.We conclude that NOS inhibitors and agmatine dose-dependently inhibit the marble-burying behavior in mice. Inhibition of nNOS seems to play a key role in the behavioral effects of NOS inhibitors, whereas agmatine seems to have a different mechanism of action. Moreover, enhancement of NO synthesis by l-arginine reversed the effect of SSRI antidepressants, further demonstrating the role of NO in regulating the marble-burying behavior.
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