Weir, RK; (2013) The role of the NK1 receptor in impulsive and perseverative behaviour in the mouse. Doctoral thesis , UCL (University College London).

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Abstract

The neurokinin-1 receptor (NK1) knockout mouse (NK1R-/-) has a hyperactive phenotype that is attenuated by psychostimulant treatment. This finding led to the NK1R-/- mouse being proposed as a model for Attention Deficit Hyperactivity Disorder (ADHD). The three core diagnostic symptoms of ADHD, hyperactivity, inattention and impulsivity have been investigated in the NK1R-/- mice alongside wildtype controls. Circular corridor apparatus was used to monitor activity over a 48-hour period, during which there was no overall difference in activity, but NK1R-/- mice displayed significantly higher levels of activity in the hour after lights out than wildtype mice. The 5-choice serial reaction time-task (5-CSRTT) is used to measure levels of attention and impulsivity (the other core features of ADHD) in wildtype and NK1R-/- mice. Both genotypes were able to learn the task to the pre-determined baseline level, but when the difficulty of the task was increased, the NK1R /- mice displayed impulsivity and deficits in attention. Interestingly, the NK1R-/- mice consistently made more perseverative responses compared to wildtype controls. This experiment was extended to test whether the phenotype of the NK1R-/- mice could be replicated with NK1 receptor antagonist treatment in wildtype animals. The NK1 receptor antagonist RP 67580 increased premature responding in wildtype animals, but did not effect omissions or perseveration. Because of the robust nature of the perseverative phenotype of the NK1R-/- at all stages of the 5-CSRTT, marble burying and burrowing tests were used as alternative behavioural paradigms to measure perseveration. In these ‘species-typical’ behavioural tests no robust difference in behaviour was noted between wildtype and NK1R-/- animals. These findings highlight the multifarious nature of perseverative behaviour and provide evidence for differential neural circuitry for perseverative behaviour in a cued task versus repetitive motor movement. Using an atlas of the distribution of the NK1 receptor and its preferred ligand substance P, this thesis concludes with explanations of the underlying neurobiology that may be responsible for these observations.

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