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

Trichotillomania (TTM) is an impulse control disorder characterized by repetitive hair pulling/trimming. Barbering behavior (BB) has been observed in laboratory animals and proposed as TTM model. The neurobiological basis of TTM is not clear, but it seems to involve striatal hyperactivity parallel to hypoactivation of prefrontal cortex. In this study we observed that knockout mice to the inducible isoform of nitric oxide synthase (NOS2) exhibit exacerbated BB following the 4th week of age, as well as increased repetitive movements compared to wild-type mice (WT). These behaviors are associated to decreased levels of NMDA receptor subunit (NR1) in prefrontal cortex, while an increase was observed in striatum of NOS2KO compared to WT. Striatal neurons from NOS2KO also exhibited increased number of branches compared to WT. The 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, attenuated the expression of BB. The silencing of NOS2 expression reduced the MAP2 (microtubule-associated protein 2) levels in activity-induced differentiated PC12 cells. Our data led us to propose that NOS2 regulates the neuronal maturation of the inhibitory afferent pathways to striatum during neurodevelopment, and such inadequate inhibition of striatal motor programs might be associated to the observed phenotype.