ebook_ADHD2019_engl.

20 Rohde, Buitelaar, Gerlach & Faraone have yet been described, but many models actually implicate both dopamine and norepinephrine neurotransmission circuits. 15 PET of the NET has been inconclu- sive, thus far. 16 Genetic studies of a number of norepinephrine receptors and the NET have not produced convincing evidence for the involvement of these genes either. 17 SEROTONIN Serotonin is involved in regulating mood and emotion, and also plays an important role in inhibition, one of the executive cognitive deficits observed in ADHD. 18 The neurons of the raphe nuclei in the midline of the brainstem are the main source of serotonin in the brain. Axons of neurons in the higher raphe nuclei spread out to the entire brain, with strong projections e.g. into the prefrontal cortex, while axons originating in the lower raphe nuclei project to cerebellum and spinal cord. Serotonin signalling is known to affect the regulation of other neurotransmitters, including that of dopamine, which may occur through several mechanisms. Neuro- transmission through serotonin was first implicated in ADHD based on paradoxi- cal calming effects of methylphenidate observed in a mouse model lacking the do- pamine transporter (DAT). The drug was shown to act by blocking the serotonin transporter in the absence of the DAT in this model. Also, other animal models with altered serotonin signalling show ADHD-like symptoms, inattention as well as hyperactivity. 18 In humans, studies have reported reduced levels of peripheral serotonin in patients with ADHD, but other studies did not find such effects. 18 The exact role of serotonin on ADHD still has to be defined in humans, however. Serotonin neurotransmission may modulate the severity of ADHD symptoms ra- ther than being related to ADHD onset. 13 Other theories suggest that it may be the comorbidity, especially with conduct disorder, obsessive compulsive disorder, aggression and mood disorders (major depression and/or anxiety), rather than the core symptoms of ADHD, which is influenced by serotonin. 18 Genetic studies of the contribution of the serotonergic system to ADHD have not been fully con- vincing, where it comes to the involvement of serotonin in ADHD. However, the serotonin receptor gene HTR1B and the gene encoding the serotonin transporter (SLC6A4, 5-HTT, SERT) have been implicated in the disorder in meta-analysis. 19 Gene by environment interactions may explain some of the observed inconsistency across studies, as the effect of stress on ADHD symptoms seems to be influenced by genetic variation in the serotonin transporter gene. 20 A recent analysis of a gene-set related to serotonergic neurotransmission suggests that variation in se- rotonergic genes may be associated with disease severity. 13 Tryptophan depletion, which causes reduction in brain 5-HT synthesis, was found associated with incre- ase of aggression, inattention, and impulsivity. 18 A retrospective pilot study on the administration of precursors of serotonin and dopamine led to promising results