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NK1 (TACR1) receptor gene 'knockout' mouse phenotype predicts genetic association with ADHD

¹ Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK
² Molecular Psychiatry Laboratory, Department of Mental Health Sciences, Royal Free & UCL School of Medicine, London, UK
³ Department of Psychological Medicine, School of Medicine, Cardiff University, Wales, UK
⁴ ADHD genetics group, MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King???s College London, UK
⁵ Department of Cell and Developmental Biology, University College London, London, UK

^* To whom correspondence should be addressed.

	Abstract

Abstract

Mice with functional genetic ablation of the Tacr1 (substance P-preferring receptor) gene (NK1R–/–) are hyperactive. Here, we investigated whether this is mimicked by NK1R antagonism and whether dopaminergic transmission is disrupted in brain regions that govern motor performance. The locomotor activity of NK1R–/– and wild-type mice was compared after treatment with an NK1R antagonist and/or psychostimulant (d-amphetamine or methylphenidate). The inactivation of NK1R (by gene mutation or receptor antagonism) induced hyperactivity in mice, which was prevented by both psychostimulants. Using in vivo microdialysis, we then compared the regulation of extracellular dopamine in the prefrontal cortex (PFC) and striatum in the two genotypes. A lack of functional NK1R reduced (>50%) spontaneous dopamine efflux in the prefrontal cortex and abolished the striatal dopamine response to d-amphetamine. These behavioural and neurochemical abnormalities in NK1R–/– mice, together with their atypical response to psychostimulants, echo attention deficit hyperactivity disorder (ADHD) in humans. These findings prompted genetic studies on the TACR1 gene (the human equivalent of NK1R) in ADHD patients in a case-control study of 450 ADHD patients and 600 screened supernormal controls. Four single-nucleotide polymorphisms (rs3771829, rs3771833, rs3771856, and rs1701137) at the TACR1 gene, previously known to be associated with bipolar disorder or alcoholism, were strongly associated with ADHD. In conclusion, our proposal that NK1R–/– mice offer a mouse model of ADHD was borne out by our human studies, which suggest that DNA sequence changes in and around the TACR1 gene increase susceptibility to this disorder.

Key Words: ADHD, d-amphetamine, dopamine, locomotor hyperactivity, methylphenidate, microdialysis, NK1R/TACR1, psychostimulant, single nucleotide polymorphism

First published on February 9, 2009, doi:10.1177/0269881108100255
This version was published on June 1, 2009


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