Title

 

Authors

S. De Fazio¹, E. Russo¹, S. Gratteri¹, M. Aribitrio², G. Trombetta³, E. Donato Di Paola¹, G. De Sarro¹.

¹Dept of Experimental and Clinical Medicine, School of Medicine, University “Magna Graecia” of Catanzaro, Catanzaro, Italy. ²National Council of Research, Institute of Neurological Science, Catanzaro, Italy. ³ASL Vibo Valentia, Mental Health Department, Vibo Valentia. 

 

Abstract

The complex relationship between mental disorders and inducible nitric oxide enzyme (iNOS) activity is actually under investigation in animals models, since circulating antibodies from schizophrenia patients act as inducers of iNOS mRNA expression in the rat frontal cortex, suggesting a role for this enzyme¹. Unfortunately, the role of antipsychotic drugs on depressive behavior which may occur together with primary psychotic symptoms or represent residual feature is less investigated. Several studies in animal models have provided insight into the   behavioral profile of atypical antipsychotic drugs (APDs), however, very few experiments have been carried out to test their antidepressant-like activity in preclinical studies. Whereas classic neuroleptics are generally ineffective in animal models of depression, some evidences suggest that atypical APDs may also act on the depressive-like responses in behavioral paradigms  through  monaminergic mechanisms². The aim of this study was to clarify the putative role of inducible iNOS derived NO in the modulation of the behavioral response in the Porsolt Forced Swimming Test (FST) after atypical or classic APDs treatment, considering an involvement for nitric oxide (NO), in the mediation of APDs effects. Methods: Adult male inducible nitric oxide synthase knock-out (iNOS-/-) mice (25-30g, 49-56 days old),  and their relative ICR  matched littermate controls (iNOS+/+) were subjected to the FST, according to the original two-day procedure described  by Porsolt³. Results: iNOS-/- mice have significantly longer immobility times than iNOS+/+ ones. In iNOS+/+ mice, single atypical APDs (quetiapine 10mg/kg; clozapine 10mg/kg; olanzapine 0.5mg/kg) administration (30 min before testing) induced a significant reduction in time spent immobile in comparison with vehicle-treated controls (32.7 ± 3.72 seconds in media), without significant differences between treated groups. Conversely aripiprazole (3 mg/kg) induced an augmentation of immobility time respect the others  atypical APDs (62± 8.15 seconds) in iNOS+/+, similarly to haloperidol. Both typical and atypical APDs induced an immobility time augmentation in iNOS-/- mice, but haloperidol and aripiprazole displayed a massive impairment in motor function. Discussion: NO seems to exert protective effect on immobility when animals are exposed to clozapine, olanzapine, and quetiapine since genetic functional inactivation of inducible nitric oxide synthase heavily affects coping behavior in mice. Aripiprazole and haloperidol do not share this property with other APDs, suggesting that the protective effect of NO on immobility might be at least in part mediated by an involvement of serotoninergic pathways rather than dopaminergic ones, since both aripiprazole and haloperidol exert blocking effect on D3 receptor subtypes.
¹Ganzinelli et al. (2010). Int J Neuropsychopharmacol. 13, 293-303.
²Weiner et al. (2003). Behav Pharmacol. 14, 215-22.
³Porsolt et al. (1977). Nature. 266, 730-732.