Inducible nitric oxide synthase (NOS2) knockout mice as a model of trichotillomania

Plinio C Casarotto; Caroline Biojone; Karina Montezuma; Fernando Q Cunha; Samia R L Joca; Eero Castren; Francisco S Guimaraes

doi:10.7717/peerj.4635

Inducible nitric oxide synthase (NOS2) knockout mice as a model of trichotillomania

PeerJ. 2018 Apr 17:6:e4635. doi: 10.7717/peerj.4635. eCollection 2018.

Authors

Plinio C Casarotto^{1

2}, Caroline Biojone^{1

3}, Karina Montezuma³, Fernando Q Cunha², Samia R L Joca³, Eero Castren¹, Francisco S Guimaraes^{2

4}

Affiliations

¹ Neuroscience Center, University of Helsinki, Helsinki, Finland.
² Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
³ Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
⁴ NAPNA: Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.

Abstract

Background: Trichotillomania (TTM) is an impulse control disorder characterized by repetitive hair pulling/trimming. Barbering behavior (BB) observed in laboratory animals is proposed as a model of TTM. The neurobiological basis of TTM is unclear, but involves striatal hyperactivity and hypoactivation of the prefrontal cortex.

Methods: In this study, we evaluated the BB in knockout mice for the inducible isoform of nitric oxide synthase (NOS2KO) and the consequences of silencing this enzyme in PC12 cell differentiation.

Results: NOS2KO exhibit exacerbated BB, starting four weeks of age, and increased repetitive movements compared to wild-type mice (WT). The expression of BB was attenuated by repeated treatment with clomipramine, a clinically approved drug to treat TTM in humans, or memantine, an antagonist of NMDA receptors, as well as partial rescue of NOS2 expression in haploinsufficient animals. The silencing of NOS2 expression reduced the MAP2 (microtubule-associated protein 2) levels in activity-induced differentiated PC12 cells.

Discussion: Our data led us to propose that NOS2 is putatively involved in the neuronal maturation of the inhibitory afferent pathways during neurodevelopment, and such inadequate inhibition of motor programs might be associated to the observed phenotype.

Keywords: Barbering; Clomipramine; Memantine; NOS2; Trichotillomania.

Grants and funding

This study was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo—Fapesp (2011/02746-4 and 2012/17626-2), Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq (471382/2011-6) and the European Research Council (iPlasticity, 322742). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.