Interaction Between Brain Histamine and Serotonin, Norepinephrine, and Dopamine Systems: In Vivo Microdialysis and Electrophysiology Study Gunnar Flik & Joost H. A. Folgering & Thomas I. H. F. Cremers & Ben H. C. Westerink & Eliyahu Dremencov Received: 24 February 2015 /Accepted: 26 February 2015 # Springer Science+Business Media New York 2015 Abstract Brain monoamines (serotonin, norepinephrine, do- pamine, and histamine) play an important role in emotions, cognition, and pathophysiology and treatment of mental dis- orders. The interactions between serotonin, norepinephrine, and dopamine were studied in numerous works; however, histamine system received less attention. The aim of this study was to investigate the interactions between histamine and oth- er monoamines, using in vivo microdialysis and electrophys- iology. It was found that the inverse agonist of histamine-3 receptors, thioperamide, increased the firing activity of dopa- mine neurons in the ventral tegmental area. Selective agonist of histamine-3 receptors, immepip, reversed thiperamide- induced stimulation of firing activity of dopamine neurons. The firing rates of serotonin and norpeinephrine neurons were not attenuated by immepip or thioperamide. Thioperamide robustly and significantly increased extracellular concentra- tions of serotonin, norepinephrine, and dopamine in the rat prefrontal cortex and slightly increased norepinephrine and dopamine levels in the tuberomammillary nucleus of the hy- pothalamus. It can be concluded that histamine stimulates se- rotonin, norepinephrine, and dopamine transmission in the brain. Modulation of firing of dopamine neurons is a key element in functional interactions between histamine and oth- er monoamines. Antagonists of histamine-3 receptors, be- cause of their potential ability to stimulate monoamine neuro- transmission, might be beneficial in the treatment of mental disorders. Keywords Histamine-3 (H 3 ) receptors . Thioperamide . Immepip . Tuberomammillary nucleus (TMN) of hypothalamus . Dorsal raphe nucleus (DRN) . Locus coeruleus (LC) . Ventral tegmental area (VTA) . Prefrontal cortex (PFC) Introduction Significant effort has recently been made in the development of agents that specifically target the histamine (HA) H 3 recep- tors for the treatment of Parkinson’ s and Alzheimer’ s disor- ders (Panula and Nuutinen 2013). However, the mechanism of action of these molecules remains unclear. Therefore, in order to understand the therapeutic potential of HA system, it is important to gain a full understanding of the function of H 3 receptors in the central nervous system (CNS). The neuroanatomy of HA system is similar to other mono- amine systems. The cell bodies of HA neurons are located in the tuberomammillary nucleus (TMN). Their projections in- nervate different areas of midbrain and telencephalon, includ- ing the dorsal raphe nucleus (DRN), locus coeruleus (LC), and ventral tegmental area (VTA), which consist of the cell bodies of 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA) neurons, respectively (Airaksinen and Panula 1988; Airaksinen et al. 1989; Iwase et al. 1993; Lin G. Flik : J. H. A. Folgering : T. I. H. F. Cremers : B. H. C. Westerink (*) : E. Dremencov Brains On-Line BV, De Mudden 16, 9747 AW, Groningen, The Netherlands e-mail: ben.westerink@brains-online.com E. Dremencov Institute of Molecular Physiology and Genetics, Slovak Academy of Science, Bratislava, Slovakia E. Dremencov Institute of Experimental Endocrinology, Slovak Academy of Science, Bratislava, Slovakia J Mol Neurosci DOI 10.1007/s12031-015-0536-3