Pillidge, KM; (2015) Predictive validity of the neurokinin-1 knockout mouse in research into Attention Deficit Hyperactivity Disorder. Doctoral thesis , UCL (University College London).

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Abstract

The neurokinin-1 receptor ‘knockout’ (NK1R-/-) mouse has been proposed as a preclinical model of Attention Deficit Hyperactivity Disorder (ADHD). Previous work from our group demonstrated that these mice are hyperactive, and display inattentiveness and impulsivity: the core signs of ADHD. The main aim of this thesis was to examine the predictive validity of the NK1R-/- mouse, by testing the effects of the ADHD treatments, guanfacine, atomoxetine and methylphenidate on ADHD-like behaviour, primarily in the 5-Choice Serial Reaction-Time Task (5-CS RTT). Guanfacine (0.1 mg/kg) improved attention in NK1R-/- mice, but not wildtypes, and did not affect anxiety-like behaviour in either genotype in the Elevated Plus Maze. This drug also reduced impulsivity in both genotypes at a higher dose (1 mg/kg), but this was likely secondary to its locomotor suppressant effect. Further studies revealed that the low dose of guanfacine improved spatial memory in NK1R-/- mice, but not wildtypes, in an object recognition task, but this effect was not mirrored by another alpha2-adrenoceptor agonist (medetomidine, at 1 – 10 tg/kg). In contrast, atomoxetine had no effect on attention, but selectively improved hyperactivity and impulsivity in NK1R-/- mice, only, at doses of 3 and 10 mg/kg, respectively. Similarly, methylphenidate (10 mg/kg) reduced two types of impulsivity (motor impulsivity and behavioural disinhibition) in NK1R-/- mice, only, but had negligible effects on attention in either genotype, when tested in an extension of the 5-CSRTT, the 5-Choice Continuous Performance Task (5C-CPT). Based on literature suggesting ADHD and obesity can be comorbid, and the finding that NK1R-/- mice were smaller, but ate more than wildtypes during the 5-CSRTT and 5C-CPT tasks, the second aim of this thesis was to determine whether NK1R-/- mice had underlying differences in body composition. Carcass composition analyses revealed that the fat content of mice depended on an interaction between genotype and gender, but bone density was increased in NK1R-/- mice compared with wildtypes. Furthermore, a comparison between two types of carcass composition analyses revealed that dual energy X-ray absorptiometry (DEXA) may over-estimate body fat by approximately 10%. Overall these studies consolidate the predictive validity of the NK1R-/- mouse model of ADHD, and highlight a role for NK1Rs in growth and body composition.

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