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Behavioural and neurochemical abnormalities in NK1 receptor knockout (NK1R-/-) mice: a novel rodent model of attention deficit/hyperactivity disorder

Yan, T; (2008) Behavioural and neurochemical abnormalities in NK1 receptor knockout (NK1R-/-) mice: a novel rodent model of attention deficit/hyperactivity disorder. Doctoral thesis , UCL (University College London). Green open access

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Abstract

NK1 receptor knockout (NK1R-/-) mice (which lack functional substance P-preferring NK1 receptors) have: (i) impaired regulation of noradrenaline (NA) release by (-adrenoceptors, and (ii) disrupted response to the rewarding effect of the psychostimulant, /-amphetamine (J-AMP). In the course of investigating whether this atypical response to d-AMP could be explained by their abnormal NA transmission, it was discovered that these mice display behavioural and neurochemical features that echo the core symptoms of Attention Deficit / Hyperactivity disorder (ADHD). The project went on to test the validity of NK1R-/- mice as a model of ADHD, using in vivo microdialysis and the Light / Dark Exploration Box (LDEB). Changes in extracellular concentration ('efflux') of monoamines and the behavioural response of NK1R-/- mice were compared with the wild-type (NK1R+/+), following an acute administration of <i-AMP or methylphenidate (MPH), which are both the first-line treatments for ADHD. Further, the possibility that a lack of functional NK.1 receptors in NK1R-/- mice could be a causal factor for these abnormalities was tested, using an acute administration of an NK1R antagonist: RP 67580 or L 733060. In the LDEB test, d-AMP and MPH increased locomotor activity of NK1R+/+ mice, but prevented the hyperactivity of NK1R-/- mice. In the microdialysis studies, basal dopamine (DA) efflux in the dorsal striatum was similar in both genotypes. After acute systemic injection of d-AMP, striatal DA efflux was increased in NK1R+/+, but not NK1R-/-, mice. This could help explain why psychostimulants do not increase arousal in ADHD. In the prefrontal cortex (PFC), basal DA efflux was > 50% lower in NK1R-/- mice, echoing the hypofrontality of ADHD patients. Systemic administration of d-AMP had no effect on cortical DA efflux in either genotype. Further, basal NA efflux in the PFC did not differ in the two genotypes, but declined in NK1R-/-, not NK1R+/+, mice when confined in the stressful light zone of the LDEB. This might echo the inattentiveness in ADHD. Finally, all these genotype differences were abolished by acute administration of an NK1R antagonist, RP 67580 or L 733060, which had no effect in NK1R-/- mice. This suggests that disruption of NK1 receptors, rather than compensatory adaptive change(s) in other neuronal systems, underlies the atypical responses of NK1R-/- mice. Collectively, the striking abnormalities of NK1R-/- mice are consistent with impaired cortico-striatal catecholamine transmission in ADHD. These findings consolidate the validity of the mutants as a rodent model of this condition, and point to the use of NK1R agonists as a novel class of drug therapy.

Type: Thesis (Doctoral)
Title: Behavioural and neurochemical abnormalities in NK1 receptor knockout (NK1R-/-) mice: a novel rodent model of attention deficit/hyperactivity disorder
Identifier: PQ ETD:593605
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis. Images identifying individuals have been redacted or partially redacted to protect their identity.
URI: http://discovery.ucl.ac.uk/id/eprint/1446267
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