ebook_ADHD2019

The World Federation of ADHD Guide 21 in 85 children and adolescents with ADHD. However, in spite of this supportive evidence for a serotonergic involvement in ADHD, findings from clinical trials with serotonin-noradrenaline reuptake inhibitors (SNRIs) such as venlaflaxine and duloxetine in adults with ADHD are rather mixed (for review, see Banerjee and Nandagopal, 2015). 18 GLUTAMATE Glutamate is the most abundant excitatory neurotransmitter in the human cen- tral nervous system and is involved in many neuronal functions including synaptic transmission, neuronal migration, excitability, plasticity, and long-term potentia- tion. 21 The fronto-striatal circuits implicated in impulsivity and compulsivity are notable for their relatively rich glutamatergic receptor density. Glutamatergic pro- jections from the various frontal subregions (orbitofrontal, infralimbic cortex, and prelimbic cortex) to the striatum (and vice versa) play a key role in the regulation of various compulsive behaviours. The signalling effect of glutamate is not depen- dent on the chemical nature of glutamate, but on how cells are programmed to res- pond when exposed to it. Because glutamate receptor proteins are expressed on the surface of the cells in such a way that they can only be activated from the out- side, glutamate exerts its neurotransmitter function from the extracellular fluid. Consequently, control of receptor activation is achieved by releasing glutamate to the extracellular fluid and then removing glutamate from it. Because there are no enzymes extracellularly that can degrade glutamate, low extracellular concentra- tions require cellular uptake. Several families of glutamate receptor proteins have been identified and classified as NMDA receptors, AMPA receptors, kainate re- ceptors, and metabotropic receptors. 22 Most, if not all, cells in the nervous system express at least one type of glutamate receptor. Several candidate genes within the glutamatergic system have been associa- ted with ADHD. For instance, associations have been found for variation in the GRIN2B gene with both inattention and hyperactivity symptoms in ADHD. A genome-wide study investigating rare variants found overrepresentation of va- riants belonging to the metabotropic glutamate receptor genes in several ADHD cohorts. 23 An analysis of a glutamate gene-set showed significant association to se- verity of hyperactivity/impulsivity of patients with ADHD. 24 Proton-magnetospec- troscopy (MRS) studies suggest a possible increase in Glx (a combination of gluta- mate, glutamine, and GABA) in the striatum across ADHD, obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD), and further, an increased Glx signal in the anterior cingulate cortex in children with ADHD and ASD but a lower Glx signal in adults with ADHD and ASD. This suggests neurodevelopmen- tal changes in fronto-striatal glutamatergic circuits across the lifespan. 25 Glutama- tergic agents such as memantine, an antagonist of he NMDA receptor, are of po-