LAUSR

&NA; Pharmacological manipulation of nitric oxide (NO) has been suggested as a promising treatment for schizophrenia symptoms. A single infusion of sodium nitroprusside, a NO donor with short half‐life, was found to improve schizophrenia symptoms. However, an increasing number of preclinical studies have demonstrated the potential beneficial effects of both NO donors and inhibitors. We investigated the potential synergistic effect of sub‐effective doses of the NO donor sodium nitroprusside or the NO inhibitor 7‐Nitroindazole (7NI) combined with clozapine, a standard atypical antipsychotic, on counteracting amphetamine or MK‐801‐induced psychosis‐like behaviors. The impact of sodium nitroprusside and 7NI on cAMP regulation in the prefrontal cortex and striatum was also evaluated. Confirming previous results, we found that both NO donors and inhibitors prevented amphetamine‐induced effects (prepulse inhibition [PPI] disruption and hyperlocomotion). In addition, we observed a synergistic effect of sodium nitroprusside and clozapine on antagonizing the disruptive effects of amphetamine, but not MK‐801, in the PPI test. The sub‐effective dose of 7NI tested did not prevent amphetamine or MK‐induced PPI effects when combined with clozapine. Interestingly, cAMP levels were significantly decreased in the prefrontal cortex after treatment with sodium nitroprusside. In the striatum, both sodium nitroprusside and 7NI blocked the amphetamine‐induced increase of cAMP. Our data corroborate previous findings on the dopaminergic mechanisms involved in the action of sodium nitroprusside. It is likely that the differential effects of sodium nitroprusside are related to its ability to modify cAMP levels in the prefrontal cortex. HighlightsNitric oxide has been suggested as a promising treatment for schizophrenia symptoms.NO donors and inhibitors prevented amphetamine‐induced behavioral effects.There is a synergistic effect of NO donor and atypical antipsychotic clozapine.NO donor and inhibitor blocked the amphetamine‐induced increase in striatal cAMP.NO donor modifies cAMP levels in both striatum and prefrontal cortex.