The NK1R-/- mouse phenotype suggests that small body size, with a sex- and diet-dependent excess in body mass and fat, are physical biomarkers for a human endophenotype with vulnerability to attention deficit hyperactivity disorder

Abstract

The abnormal behaviour of NK1R-/- mice (locomotor hyperactivity, inattentiveness and impulsivity in the 5-Choice Serial Reaction-Time Test) is arguably analogous to that of patients with attention deficit hyperactivity disorder (ADHD). Evidence suggests that small body size and increased body weight are risk factors for ADHD. Here, we compared the body size, body mass and body composition of male and female NK1R-/- mice and their wildtypes that had been fed either standard laboratory chow or a high-fat (45%: ‘Western’) diet. Male NK1R-/- mice from both cohorts were approximately 7% shorter than wildtypes. A similar trend was evident in females. Male NK1R-/- mice fed the normal diet weighed less than wildtypes but the ‘body mass index’ (‘mBMI’: weight (mg)/length (cm)2) of female NK1R-/- mice was higher than wildtypes. When given the high-fat diet, the mBMI of both male and female NK1R-/- mice was higher than wildtypes. There were no consistent genotype or sex differences in protein, ash or water content of mice from the two cohorts. However, the fat content of male NK1R-/- mice on the Western diet was considerably (35%) higher than wildtypes and resembled that of females from both genotypes. We conclude that a lack of functional NK1R is associated with small body size but increases vulnerability to an increase in mBMI and fat content, especially in males. This phenotype could also be evident in ADHD patients with polymorphism(s) of the TACR1 gene (the human equivalent of Nk1r).

Sex: A change in our guidelines to authors to ensure that this is no longer an ignored experimental variable

“…A focus upon sex driving diversity in drug response is also evident from the literature: Recent examples include that airway smooth muscle, isolated from obese females, manifests greater agonist‐induced excitation–contraction coupling than those derived from lean males, females, or from obese males (Orfanos et al, 2018) and that sex differences in the thermoregulatory and behavioural responses to the CNS stimulant, cathinone (Alsufyani & Docherty, 2017), have been identified. However, a notable complication is that the response of interest can depend on an interaction between sex and genotype, as was the case for the vulnerability to obesity in a strain of genetically altered mice (Pillidge, Heal, & Stanford, 2016).…”

Mental health dished up—the use of iPSC models in neuropsychiatric research

“…This gene has already been associated with psychiatric disorders such as anxiety (Muñoz and Coveñas 2014 ) and addiction (Schank 2014 ). However, in animal models this gene increases the risk of high BMI, which is at odds with AN presentation (Pillidge et al 2016 ). Therefore it remains unclear as to what, if any role, tachykinin signaling may play in AN etiology.…”

Modeling anorexia nervosa: transcriptional insights from human iPSC-derived neurons

“…While TACR1 has been implicated in a variety of animal models that recapitulate core phenotypes of AN such as heightened anxiety and hyperactivity, 78 , 86 , 87 absence of TACR1 also increases risk for high body mass index in a sex-dependent manner in mice. 88 Conversely, increased TACR1 expression in human females with AN presumably increases risk for low body mass index. Among its diverse biological roles, TACR1 antagonists have been developed to treat emesis and reduction in food intake in those receiving cisplatin chemotherapy.…”