Slone-Murphy, J.; (2011) Behavioural and molecular responses to amphetamine in the neurokinin-1 receptor knock-out mouse. Doctoral thesis , UCL (University College London).

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Abstract

The neurokinin-1 receptor knock-out (NK1R-/-) mouse is hyperactive and shows deficits in attentional processing, and has recently been put forward as a model of attention deficit hyperactivity disorder (ADHD). Acute amphetamine, a first-line treatment for ADHD and a drug of abuse, paradoxically reduces the hyperactivity of NK1R-/- mice, and the characteristic amphetamine-stimulated increase in striatal dopamine efflux seen in wild-type animals is attenuated in NK1R-/- mice. The research presented in this thesis centres on the behavioural and molecular responses of NK1R-/- mice to amphetamine. Over the course of this work, a fundamental deficit in the striatal cholinergic neuroanatomy of NK1R-/- and wild-type mice was discovered. While the responses of NK1R-/- mice to amphetamine were normal compared with wild-types, NK1R-/- mice were found to have a reduced number of cholinergic interneurones in the lateral striatum, independent of treatment, and an increased number of cholinergic neurons in the nucleus basalis. In the striatum, the reduction in cell numbers was specific to cholinergic interneurones, which all express the NK1 receptor in wild-type animals and play a key role in regulating striatal dopamine release. The number of striatal parvalbumin-expressing interneurones, which do not express NK1 receptors, did not differ between NK1R-/- and wildtype mice. The present results demonstrate that global disruption of the NK1 receptor results in significant alterations in central cholinergic system neuroanatomy, which may contribute to the previously observed impaired dopaminergic response to amphetamine. The results presented in this thesis provide support for emerging evidence that deficits in cholinergic transmission play a role in the pathophysiology of ADHD, and could have significant implications for future ADHD research.

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