Dudley, JA; (2013) Evaluation of the Neurokinin-1 receptor knockout mouse model of Attention Deficit Hyperactivity Disorder. Doctoral thesis , UCL (University College London).

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Abstract

Attention Deficit Hyperactivity Disorder (ADHD) is a common neurobehavioural disorder in children and often persists into adulthood. Current treatments lack efficacy in a large number of patients, and the aetiology of ADHD needs to be further elucidated in order to develop alternative treatments. The neurokinin-1 receptor knockout (NK1R-/-) mouse has recently been proposed as an animal model of ADHD; it is hyperactive and this is reduced by psychostimulants, polymorphisms in the TACR1 gene (the human NK1R gene) have been found in patients with ADHD, and NK1R-/- mice have deficits in monoamine transmission, consistent with the pathophysiology of ADHD. Finally, the NK1R-/- mouse exhibits inattentiveness, impulsivity and perseveration in the 5-Choice Serial Reaction-Time Task (5-CSRTT). The aim of this thesis was to further validate the NK1R-/- mouse model of ADHD by studying the effects of d-amphetamine on its performance in the 5-CSRTT, and subsequently to test alternative drugs that could be therapeutically beneficial. However, over the course of this work, the hyperactivity of NK1R-/- mice was not stable when tested acutely. Therefore, telemetry was used to monitor the activity of mice in their homecage over many days. Also, the breeding method was expanded to include heterozygous matings in order to minimise genetic drift. Whilst hyperactivity in this test was robust in both colonies, the impulsivity seen in NK1R /- mice bred from homozygous matings was not present in NK1R-/- mice bred from heterozygotes. Furthermore, there was a reduction in choline acetyltransferase-positive cells in the striatum of homozygously-bred but not heterozygously-bred NK1R-/- mice. These findings highlight important interactions between early environment, NK1R function and the central cholinergic system. They also support evidence suggesting that abnormal cholinergic transmission is involved in ADHD, and could underlie impulsivity. Finally, these findings could have important implications for future research on impulse control disorders.

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