title: Inhibition of iNOS induces antidepressant-like effects in mice: pharmacological and genetic evidence.
abstract: Recent evidence has suggested that systemic administration of non-selective NOS inhibitors induces antidepressant-like effects in animal models. However, the precise involvement of the different NOS isoforms (neuronal-nNOS and inducible-iNOS) in these effects has not been clearly defined yet. Considering that mediators of the inflammatory response, that are able to induce iNOS expression, can be increased by exposure to stress, the aim of the present study was to investigate iNOS involvement in stress-induced behavioral consequences in the forced swimming test (FST), an animal model sensitive to antidepressant drugs. Therefore, we investigated the effects induced by systemic injection of aminoguanidine (preferential iNOS inhibitor), 1400W (selective iNOS inhibitor) or n-propyl-l-arginine (NPA, selective nNOS inhibitor) in mice submitted to the FST. We also investigated the behavior of mice with genetic deletion of iNOS (knockout) submitted to the FST. Aminoguanidine significantly decreased the immobility time (IT) in the FST. 1400W but not NPA, when administered at equivalent doses considering the magnitude of their Ki values for iNOS and nNOS, respectively, reduced the IT, thus suggesting that aminoguanidine-induced effects would be due to selective iNOS inhibition. Similarly, iNOS KO presented decreased IT in the FST when compared to wild-type mice. These results are the first to show that selective inhibition of iNOS or its knockdown induces antidepressant-like effects, therefore suggesting that iNOS-mediated NO synthesis is involved in the modulation of stress-induced behavioral consequences. Moreover, they further support NO involvement in the neurobiology of depression. This article is part of a Special Issue entitled 'Anxiety and Depression'.
authors.affiliation: Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil.
authors.forename: Karina
authors.initials: K
authors.lastname: Montezuma
authors.forename: Caroline
authors.initials: C
authors.lastname: Biojone
authors.forename: Sabrina F
authors.initials: SF
authors.lastname: Lisboa
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Francisco S
authors.initials: FS
authors.lastname: Guimarães
authors.forename: Sâmia R L
authors.initials: SR
authors.lastname: Joca
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D003863:Depression / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D007099:Imipramine / Q000494:pharmacology / Q000627:therapeutic use; D046353:Immobility Response, Tonic / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D013550:Swimming / Q000523:psychology
chemical_list: D000928:Antidepressive Agents; D004791:Enzyme Inhibitors; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D007099:Imipramine