ebook_ADHD2019_engl.

The World Federation of ADHD Guide 19 research of mechanisms underlying ADHD. In animal models, knock-out of the Dat1 gene produces elevated dopaminergic tone and hyperactivity in the mouse; 9 the latter is also observed upon knock-down of the dopamine transporter in the fruit fly Drosophila melanogaster. 10 Implicating the dopaminergic system in ADH- D-like behaviour is also the neonatal 6-hydroxy-dopamine lesioned rat model. 11 Neuroimaging studies of the dopamine transporter in humans using positron emis- sion (PET) suggest that more dopamine transporter activity is present in people with ADHD than in healthy individuals, 12 and evidence for depressed dopamine signalling has also been concluded from alterations in dopamine receptors seen in PET. Evidence for disturbances in dopamine signalling have also been suggested by findings of genetic studies. Here, it has again been the dopamine transporter, and in particular a genetic polymorphism in the 3’-regulatory region of the DAT1 gene, that has been the subject of most studies. Meta-analyses have shown signifi- cant associations of this genetic variation in the gene, albeit different versions of the gene were found associated with the disorder in children and adults. Further- more, an analysis of genetic variants in a larger group of genes involved in ADHD suggested association of this set of genes with the severity of symptoms in children with the disorder. 13 NOREPINEPHRINE Norepinephrine signalling is intimately linked to the dopamine system by the fact that norepinephrine is a downstream product of the metabolism of dopamine. Norepinephric neurotransmission regulates important higher cognitive functions such as working memory and inhibitory control, primarily through its projections originating in the locus coeruleus and innervating multiple areas of the cortex, the thalamus, and cerebellum. 5 Especially the innervation of the prefrontal cor- tex (PFC) by norepinephrine pathways is thought to be important for understan- ding ADHD. Norepinephrine and dopamine signalling are intimately linked in PFC, i.e. they influence each other in optimizing PFC performance in cognitive tasks. 14 Knowledge about the role of norepinephrine in ADHDmainly comes from the fact that MPH and dexamphetamine inhibit the norepinephrine transporter (NET) in addition to the DAT. 14 Moreover, atomoxetine, a selective NET inhi- bitor, is effective in the treatment of the cardinal symptoms of ADHD and some of its comorbidities, as are several other prescription drugs with noradrenergic properties, like guanfacine and clonidine 5 While this is clear evidence that altering norepinephrine signalling can ameliorate the symptoms of ADHD, less evidence is available to link it to ADHD neurobiology. This may primarily be due to the concentration of research on the dopaminergic pathways, and the large overlap between dopamine and norepinephrine synthesis and function. No animal models for ADHD based on altering genes involved directly in norepinephrine signalling