Tourette s syndrome TS is a neurobehavioral disorder

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). Obesity is one of the worldwide concerns, with high prevalence and adverse effects on human health and life expectancy. According to the World Health Organization (WHO), obesity is defined as abnormal or excessive fat accumulation in the body with body mass index (BMI) of 30 or more. Obesity increases the risk of serious health problems such as cardiovascular disease, cancer, diabetes type 2, and obstructive sleep NS 11021 mg (Berlin et al., 2011; Leurs et al., 2005; Passani, Blandina, & Torrealba, 2011; Sander et al., 2008). Metabolic homeostasis establishes a balance between food intake and energy expenditure through a large number of pathways in the body. Appetite and satiety are two critical components of eating behavior, which is regulated by a large number of orexigenic and anorexigenic signaling pathways in the central and peripheral nervous systems (Berlin et al., 2011; Lee et al., 2008; Passani et al., 2011; Sandoval, Cota, & Seeley, 2008). Several investigations reflect the paramount role of neuronal histamine in feeding behavior mediated by central H3 and H1 receptors. Loss of appetite and reduced body weight have been observed in response to elevated hypothalamic histamine levels in rodent models following the blockade of H3 autoreceptors (Leurs et al., 2005; Passani et al., 2011; Plancher, 2011; Singh & Jadhav, 2013). Interestingly, the other side of the histamine action on modulating the eating behavior occurs through central H1 receptors, whose stimulation suppresses food intake and leads to weight loss in rodents. This is the main reason behind the growing interest in developing H3R antagonists as anti-obesity therapeutic agents. However, there is a controversy about the exact mechanism of H3R involvement in the feeding process as few reports indicate H3R-induced anorexia in animal models (Berlin et al., 2011; Passani et al., 2011; Schlicker & Kathmann, 2017) and conflicting observations also described reduced food-intake in mice followed by H3R activation with imetit as agonist (Yoshimoto et al., 2006). More clarification in this area is therefore needed. Drug addiction is a compulsive multifaceted behavior which is characterized by continuous consumption of drugs in an out of control manner. Although it is believed that mesolimbic dopaminergic system underlies in dopamine hypothesis of drug addiction, the role of histaminergic system on psychomotor and rewarding effects of addictive drugs should not be ignored (Brabant, Alleva, Quertemont, & Tirelli, 2010; Ellenbroek & Ghiabi, 2014; Vohora & Bhowmik, 2012). Studies have demonstrated that dopamine transmission can be reduced by histamine via presynaptic and postsynaptic H3R located on dopaminergic and GABAergic neurons in striatum (C. Brabant et al., 2010; Vohora & Bhowmik, 2012). There are some lines of evidence indicating the effectiveness of H3R antagonist/inverse agonists in alcohol abuse in animal models in preclinical studies (Galici et al., 2011; Nuutinen et al., 2016; Nuutinen, Vanhanen, Maki, & Panula, 2012; Rezvani, Lawrence, Arolfo, Levin, & Overstreet, 2012; Vanhanen et al., 2013). It has been observed that direct antagonizing of dopamine receptors is associated with some limitations including inefficacy and adverse effects, therefore, H3R antagonist/inverse agonists can be potential alternative agents in drug abuse.