br Acknowledgments This study was

Acknowledgments This study was financially supported by National Science Center Poland grant No DEC-2011/02/A/NZ4/00031 (KKK), Jagiellonian University Medical College (Poland) grants: K/ZDS/007130 (SM) and K/ZDS/007131 (SM), COST Action CA15135 (DŁ, HS, KKK) and DFG INST 208/664-1 FUGG (HS). Thanks to students: Anna Fatel and Jarosław Kubczyk for their contribution in the synthesis work and Mateusz Kozłowski for his contribution in the preparation of histamine H4 receptor model. All in vivo experimental protocols were conducted according to guidelines of ICLAS (International Council on Laboratory Animal Science) and approved by the First Local Ethics Committee on Animal Testing at the Jagiellonian University in Kraków (105/2016).
Introduction As an aminergic multifunctional neurotransmitter, histamine [2-(4-1H-imidazolyl)ethylamine] plays versatile roles in a wide variety of physiological processes and is therefore also implicated in several pathological conditions (Celanire, Wijtmans, Talaga, Leurs, & de Esch, 2005; Gemkow et al., 2009; Nikolic, Filipic, Agbaba, & Stark, 2014). Histamine is produced in a large number of tissues by cells such as mast cells, parietal cells of the gastric mucosa, and neurons of central/peripheral nervous system via decarboxylation of L-histidine by histidine decarboxylase (HDC). Histamine inactivation occurs via two major metabolic pathways, N-methylation and oxidation. In mammalian brain histamine N-methyltransferase (HNMT) catalyzes the methylation of histamine to the H3R inactive Nτ-methylhistamine, whereas monoamine oxidase and aldehyde oxidase are responsible for the formation of (Nτ-methyl)imidazole acetic formyl peptide receptors by the metabolic oxidation of histamine and to some extent of Nτ-methylhistamine (Berlin, Boyce, & Ruiz Mde, 2011; Lemke, Williams, & Foye, 2013). Histamine exerts its actions through the activation of four distinct receptor subtypes (H1 to H4), that belong to the class A family of G protein-coupled receptors (GPCRs) (Leurs, Bakker, Timmerman, & de Esch, 2005; Nikolic et al., 2014). Among the histamine receptors, the H3 receptor (H3R) is a pre-synaptically located autoreceptor that inhibits the synthesis and release of histamine. In addition, H3Rs function as pre-synaptic heteroreceptors with inhibitory activity on the release of several neurotransmitters, namely acetylcholine, γ-aminobutyric acid (GABA), dopamine, serotonin, noradrenaline and glutamate (Esbenshade et al., 2008). The H3R was discovered in 1983 by Arrang et al. by analyzing the inhibition of histamine release in depolarized slices of rat cerebral cortex (Arrang, Garbarg, & Schwartz, 1983). In 1987, the presence of the receptor was confirmed by the development of R-α-methylhistamine and thioperamide as selective H3 receptor agonist and antagonist, respectively (Arrang et al., 1987). Later, in 1999 Lovenberg and co-workers cloned the gene of the human H3R, which code for a 445 amino acid protein (Lovenberg et al., 1999). The H3R is predominantly concentrated in the central nervous system (CNS); however, it is also expressed peripherally in the gastrointestinal tract, the airways, and the cardiovascular system (Celanire et al., 2005; Tiligada, Zampeli, Sander, & Stark, 2009). The H3R couples to Gαi/o proteins, and hence its stimulation leads to inhibition of adenyalate cyclases, diminishing the level of cyclic AMP (cAMP) with the subsequent reduction in downstream signaling pathways such as protein kinase A (PKA) activation and cAMP-responsive element binding protein (CREB)-induced gene transcription. The Gβγ complexes of Gαi/o proteins inhibit the opening of voltage-activated calcium channels, thereby reducing neurotransmitter release (Nieto-Alamilla, Marquez-Gomez, Garcia-Galvez, Morales-Figueroa, & Arias-Montano, 2016). Like other histamine receptors, H3R forms receptor heterodimers shown for dopamine D1 and D2 receptors so far (Ferrada et al., 2008; Vohora & Bhowmik, 2012). Thereby, decreased affinity of D2 receptor ligands could be observed in presence of H3R agonists in vitro as well as potentiation of D1 and D2 receptor mediated locomotor activity by application of the H3R inverse agonist/antagonist thioperamide (Ferrada et al., 2008). Other effector proteins activated by H3R stimulation include mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3K) and phospholipase A2 (PLA2) producing arachidonic acid. MAPK and PI3K signaling pathways are associated with the phosphorylation of extracellular signal-regulated kinases (ERKs) and protein kinase B (PKB), respectively, and the latter inhibits glycogen synthase kinase-3β (GSK-3β). H3R activation also inhibits the activity of the Na+/H+ exchanger (Bhowmik, Khanam, & Vohora, 2012; Leurs et al., 2005).