ebook_ADHD2019_engl.

22 Rohde, Buitelaar, Gerlach & Faraone tential value in the treatment of impulsivity in children and adolescents, including ADHD, but large-scale positive trials have not been published yet. HISTAMINE Histamine is one of the key neurotransmitters regulating arousal and attention. The cell bodies of histamine neurons are found in the posterior hypothalamus, in the tuberomammillary nuclei. From here, these neurons project throughout the brain, including to the cortex, through the medial forebrain bundle. Histamine neurons increase wakefulness and prevent sleep. 26 In addition, this neurotransmit- ter is an important agent in (neuro)immune reactions. Interest in the role of hista- mine in ADHD stems from the observations that allergies have an increased inci- dence in people with ADHD. Indeed, a recent meta-analysis shows that children with ADHD are more likely to develop asthma, allergic rhinitis, atopic dermatitis, and allergic conjunctivitis than healthy individuals. 27 Conversely, children with al- lergies appear to have higher ADHD symptom ratings than non-affected children. The histamine H3 receptor subtype is mainly distributed in the central nervous system and functions as both a presynaptic autoreceptor that reduces histamine release and a heteroreceptor that regulates release of other neurotransmitters. Histamine H3 receptor antagonists and inverse agonists increase release of brain histamine and other neurotransmitters. The H3 receptor antagonists have been shown to promote arousal in various species, without the psychomotor activation seen with stimulants. 28 Potent histamine H3 receptor antagonists are currently being developed and tested for the treatment of ADHD. 29 NICOTINIC ACETYLCHOLINERGIC SYSTEM Nicotinic acetylcholine receptors are receptor proteins that respond to the neuro- transmitter acetylcholine. Nicotinic receptors also respond to drugs, including the nicotinic receptor agonist nicotine. Nicotine use has been associated with impro- vement in cognition, attention in particular, in different animal species, healthy human volunteers, and patients with ADHD. 30 In addition to the knowledge about the influence of attention, the nicotinic acetylcholine neurotransmission system is also implicated in ADHD through genetic findings: a large study of copy num- ber variants found duplications of the gene encoding the a 7-nicotinic acetylcho- line receptor (CHRNA7), located in the mutation-prone region on chromosome 15q13.3, to contribute to the risk for the disorder. 31 The nicotinic acetylcholine system may be one of the new targets for the development of alternative drugs for ADHD. Nicotine appears to exert its beneficial effect selectively on behavioural inhibition and delay aversion tasks, which are known to have good discriminant