NK1 (TACR1) Receptor Gene ‘Knockout’ Mouse Phenotype Predicts Genetic Association with ADHD
| Autor: | Stephen P. Hunt, Anita Thapar, Hugh Gurling, Philip Asherson, SC Stanford, Andrew McQuillin, TC Yan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Male
Dopamine psychostimulant methylphenidate Gene mutation Mice 0302 clinical medicine single nucleotide polymorphism Pharmacology (medical) Prefrontal cortex Mice Knockout 0303 health sciences Methylphenidate Dopaminergic Dextroamphetamine Receptors Neurokinin-1 3. Good health Psychiatry and Mental health Phenotype Knockout mouse Psychology medicine.drug medicine.medical_specialty microdialysis Prefrontal Cortex locomotor hyperactivity Motor Activity Polymorphism Single Nucleotide 03 medical and health sciences Internal medicine medicine Attention deficit hyperactivity disorder ADHD Animals Humans Genetic Predisposition to Disease 030304 developmental biology Pharmacology Original Paper Base Sequence medicine.disease Corpus Striatum Mice Inbred C57BL Endocrinology Attention Deficit Disorder with Hyperactivity Case-Control Studies Neuroscience 030217 neurology & neurosurgery NK1R/TACR1 d-amphetamine |
| Zdroj: | Journal of Psychopharmacology (Oxford, England) |
| ISSN: | 1461-7285 0269-8811 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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