THE NITRIC OXIDE (NO) DONOR MOLSIDOMINE COUNTERACT BEHAVIOURAL DEFICITS RESEMBLING NEGATIVE SYMPTOMS AND COGNITIVE DEFCITS IN THE RAT

Abstract Background The deficiency of the gaseous molecule nitric oxide (NO) seems to be critically involved in the pathogenesis of schizophrenia. Thus, molecules that can normalize NO levels as are the NO donors, might be of utility for the medication of this psychiatric disease. Aims & Objectives The aim of the present study was to detect the ability of the NO donor molsidomine to reduce schizophrenia-like impairments produced either by blockade of the N-methyl-D-aspartate (NMDA) receptor or by dysregulation of the brain dopaninergic system in the rat. Method Molsidomine's ability to attenuate social withdrawal and spatial recognition memory deficits induced by the NMDA receptor antagonist ketamine were assessed using the social interaction and the object location test, respectively. Further, the ability of molsidomine to attenuate spatial recognition and emotional memory deficits induced by the dopaminergic agonist apomorphine was evaluated among the object location and the step-through passive avoidance test, respectively. Finally the efficacy of the combination of sub-threshold doses of molsidomine with sub-effective doses of the atypical neuroleptics clozapine and risperidone to attenuate non-spatial recognition memory impairments caused by treatment either of ketamine or apomorphine was also assessed using the object recognition test. Results Molsidomine (2 and 4 mg/kg) attenuated ketamine-induced social withdrawal and counteracted spatial recognition and emotional memory deficits induced either by ketamine or apomorphine. Further, the joint administration of inactive doses of molsidomine (1 mg/kg) with those of clozapine (0.1 mg/kg) and risperidone (0.03 mg/kg) counteracted non-spatial recognition memory deficits caused either by ketamine or apomorphine. Discussion & Conclusions The present results indicate that molsidomine is sensitive to glutamate hypofunction since it attenuated behavioural deficits in animal models mimicking the negative symptoms and cognitive impairments of schizophrenia. Additionally, the current findings propose that molsidomine is sensitive to dopaminergic dysfunction since it reduced cognitive defcits induced by apomorphine. Finally, the findings here reported support the potential of molsidomine as an adjunctive drug for the therapy of schizophrenia.