Porter, AJ; (2015) The Role of the Neurokinin-1 Receptor in Behaviour and Cognition: an interaction with the Brain Renin Angiotensin System and its implications for Attention Deficit Hyperactivity Disorder. Doctoral thesis , UCL (University College London).

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Abstract

Mice lacking functional neurokinin-1 receptors (NK1R-/-) display several behavioural abnormalities that resemble Attention Deficit Hyperactivity Disorder (ADHD), including locomotor hyperactivity (which is alleviated by ADHD medication), impulsivity and inattentiveness. These findings prompted the proposal that NK1R-/- mice offer a novel murine model of ADHD. The first aim of this thesis was to investigate the influence of non-genetic (epigenetic/environmental) factors on the behaviour of NK1R-/- mice by comparing animals from two different breeding protocols. These studies revealed that certain elements of their impulsivity are influenced by non-genetic factors, but other behaviours are not. The second aim was to compare the behaviour of male and female animals, to determine whether there are sex differences in their behaviour. This study revealed that the hyperactivity of NK1R-/- mice is not evident in females, echoing typical sex differences in ADHD patients. Following this, the behavioural effects of several drugs that target the brain renin angiotensin system (BRAS) are reported. This was prompted by preliminary evidence that the BRAS and NK1R interact in the regulation of locomotor activity. The angiotensin converting enzyme (ACE) inhibitor, captopril, abolished the hyperactivity and impulsivity of (male) NK1R-/- mice, suggesting that ACE could provide a novel therapeutic target for the treatment of ADHD. By contrast, angiotensin receptor antagonism either exacerbated or had no effect on these behaviours, suggesting that captopril's therapeutic effect is not due to a reduction in angiotensin II. Finally, the performance of NK1R-/- mice in the 5-Choice Continuous Performance Test was investigated. NK1R-/- mice displayed performance deficits only during certain phases of training, suggesting that detection of the impulsive or inattentive phenotype might require unpredictable test parameters. Overall, these studies further validate/phenotype the NK1R-/- mouse model of ADHD, and point to an interaction between the BRAS and NK1R in the regulation of ADHD-related behaviours, which warrants further investigation.

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