Abstract
BackgroundTrichotillomania (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.MethodsIn 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.ResultsNOS2KO 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.DiscussionOur 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.
Highlights
The cortico-striato-thalamo-cortical circuitry (CSTC) is a series of reverberatory loops that control motor programs
Analysis by two-way ANOVA indicates a significant effect of the genotype [F (1,105) = 99.87, p < 0.0001], the age [F (6,105) = 34.14, p < 0.0001], and interaction between these factors [F (6.105) = 5.23, p < 0.0001] on the barbering behavior exhibited by NOS2 knockout (NOS2 KO) compared to NOS2 haploinsufficient animals from weaning age, Fig. 1D
The present study suggests that the increased barbering behavior (BB) of NOS2 KO mice could be a putative model of trichotillomania (TTM)
Summary
The cortico-striato-thalamo-cortical circuitry (CSTC) is a series of reverberatory loops that control motor programs. The glutamatergic neurotransmission plays a crucial role in both afferent and efferent pathways in prefrontal cortex and striatum, two core structures in the regulation of CSTC (Langen et al, 2011a; Langen et al, 2011b) In this scenario, nitric oxide (NO) plays a major part, regulating the release of glutamate and in. This later feature of NO is apparently mediated by the inducible isoform of nitric oxide synthase (NOS2) (Arnhold et al, 2002). 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
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