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  • The relationship between the attention deficit hyperactivity

    2021-12-01

    The relationship between the attention deficit hyperactivity disorder (ADHD) and H3Rs is supported by several reports (Berlin et al., 2011; Passani, Bacciottini, Mannaioni, & Blandina, 2000; Vohora & Bhowmik, 2012). ADHD is a neurobehavioral disorder with high prevalence in children, with hyperactivity, inattention, impulsivity, agitation, and disorganized behavior as the most common symptoms. The exact mechanisms of ADHD are not clearly understood; however, it may arise from the dysfunction of noradrenergic and dopaminergic signaling. The most routinely used therapeutic agents for ADHD treatment are methylphenidate and atomoxetine as stimulant and non-stimulant agents, respectively. Although it seems that these agents increase norepinephrine and dopamine concentrations in neuronal synapses, there is evidence that histamine levels in the prefrontal cortex are also augmented. Since these drugs have significant adverse effects and great potential of being abused, H3R antagonists may represent a suitable alternative to the current therapeutics (Berlin et al., 2011; Passani et al., 2000). In addition, the neural histaminergic system is involved in schizophrenia. This disorder is originated by hyperactivity of the dopaminergic system, with psychotic symptoms such as hallucination, delusion, emotional pauperism, and lack of motivation (Sander et al., 2008; Vohora & Bhowmik, 2012). The currently used pharmacotherapy for schizophrenia focuses on antagonizing dopamine receptors, mainly D2 receptors, but extrapyramidal symptoms and metabolic actions (i.e. weight gain) are adverse effects associated with D2 receptor antagonists (Sadek, Saad, Sadeq, et al., 2016). Some studies show that Nτ-methylhistamine is enhanced in the cerebrospinal fluid of schizophrenic patients (Rapanelli & Pittenger, 2016; Sander et al., 2008), and abnormal H3R expression is observed in the 821 of schizophrenic individuals (Rapanelli & Pittenger, 2016). In this context, compounds with inhibitory activity on H3Rs receptors can be promising agents to replace the pharmaceuticals in use. Besides, an additional benefit of H3R antagonists would be the induction of glutamate release, as glutamatergic hypoactivity is observed in this neuropsychiatric condition (Ellenbroek & Ghiabi, 2014). Tourette's syndrome (TS) is a neurobehavioral disorder characterized by chronic motor and vocal tics. The histaminergic system appears to be implicated in the pathophysiology of TS because H3R up-regulation has been observed in the striatum of HDC knock-out animal models (Rapanelli et al., 2017; Rapanelli & Pittenger, 2016). Therefore, H3Rs can be targeted by antagonists that eliminate the action of autoreceptors leading to enhanced histamine synthesis and release (Bloch, State, & Pittenger, 2011; Thenganatt & Jankovic, 2016). With a prevalence of about 6 per 1000, Epilepsy is a frequent disease characterized by transient seizures due to abnormal synchronous or excessive activity of neurons (Fiest et al., 2017; Fisher et al., 2005; Fisher et al., 2014). Though the etiology of this disease is unknown in most cases, a disbalance between excitatory (namely glutamate) and inhibitory (GABA) neurotransmitter systems is commonly hypothesized to trigger epileptiform discharges resulting in epileptic seizures with differing onset (Fisher et al., 2017; Naylor, 2010). On a molecular level, the relationship to histamine seems to rest upon the H3R mediated regulation of glutamate and GABA release and, inversely, their modulation of histamine release in brain (Bhowmik et al., 2012; Okakura, Yamatodani, Mochizuki, Horii, & Wada, 1992; Okakura-Mochizuki, Mochizuki, Yamamoto, Horii, & Yamatodani, 1996). From in vivo rodent models the involvement of brain histaminergic system is demonstrated by the anticonvulsant activity of H3R antagonists and histidine as histamine precursor as well as the competence of histamine H1 receptor antagonists to reverse these inhibiting effects (Lazewska et al., 2018; Sadek et al., 2016; Svob Strac et al., 2016).