RATIONALE: That exaggerated production of the gaseous molecule nitric oxide (NO) is associated with the pathogenesis of schizophrenia is well-documented. Therefore, compounds that can adjust nitrergic activity such as NO synthase (NOS) inhibitors might be useful for the treatment of schizophrenia.
OBJECTIVES: The purpose of the current study was to investigate in the rat the ability of the neuronal NOS (nNOS) inhibitor 7-nitroindazole (7-NI) in counteracting schizophrenia-like-deficits caused by blockade of the N-methyl-D-aspartate (NMDA) receptor.
METHODS: 7NI's capacity to attenuate social withdrawal, disruption of emotional and recognition memory induced by NMDA receptor antagonists, namely ketamine and MK-801, were evaluated using the social interaction, the step-through passive avoidance, the object recognition and the object location tests. The efficacy of the joint administration of sub-threshold doses of 7-NI with those of the atypical neuroleptics clozapine and risperidone in attenuating recognition memory deficits induced by ketamine was also tested.
RESULTS: 7-NI (1 and 3 mg/kg) alleviated social withdrawal caused by ketamine (8 mg/kg), abolished emotional memory impairments caused by MK-801 (0.1 mg/kg) and counteracted ketamine (3 mg/kg)-induced recognition memory deficits. Finally, co-administration of inactive doses of 7-NI (0.1 mg/kg) with those of clozapine (0.1 mg/kg) or risperidone (0.03 mg/kg) reduced the detrimental effects of ketamine (3 mg/kg) on recognition memory.
CONCLUSIONS: The present results indicate that 7-NI is sensitive to glutamate blockade since it decreased behavioural impairments resembling the negative symptoms and cognitive deficits of schizophrenia. Moreover, these findings corroborate the potential of 7-NI as an adjunctive molecule for the medication of schizophrenia.
