Modulation of behavior by the histaminergic system: Lessons from H1R-and H2R-deficient mice

Abstract

Besides acting in the immune system, histamine is also a neurotransmitter in the central nervous system. The H1R causes central side effects, e.g. of first generation antihistamines, antidepressants or antipsychotics and represents the component of the central histaminergic system most extensively studied in behavior experiments with knock-out mice. Central effects of H2R are similar, but only few behavioral results from knockout models are available. We summarize the behavior phenotype of H1R- and H2R-deficient mice, revealing histaminergic modulation of behaviors like locomotor activity, cognition, emotional states, arousal, sleep and wakefulness, circadian rhythm, pain perception, food intake and energy consumption, respiration and susceptibility to seizures. Knock-out models demonstrate several central effects of H1R and H2R that are not clinically and therapeutically exploited to date. We critically discuss problems and pitfalls of both the knock-out mouse technique and the pharmacological approach with receptor-selective ligands. The behavioral characterization of Hrh1(-/-)- and Hrh2(-/-)-mice is crucial, because many pharmacological agents lack the required selectivity to unequivocally address the functions of a single histamine receptor subtype.

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…Mice deficient in H 2 receptor function display cognitive deficits, an impairment in hippocampal long-term potentiation (Dai et al, 2007), and abnormalities in nociception (Mobarakeh et al, 2005(Mobarakeh et al, , 2006, gastric, and immune functions (Jutel et al, 2001;Teuscher et al, 2004;Schneider et al, 2014a). The suppression of immune responses via the H 2 receptor was not only shown in H 2 receptor-deficient mice but also in human antigen presenting cells, where H 2 receptor stimulation resulted in the downregulation of numerous cytokines (Gutzmer et al, 2005;Glatzer et al, 2013).…”

The histamine H4-receptor and the central and peripheral nervous system: A critical analysis of the literature

“…Both H 1 R and H 2 R modulate Th1/Th2 T cell polarization (Jutel et al, 2009). Importantly, histamine also acts as a neurotransmitter and is produced by neurons of the tuberomamillary nucleus, which sends neuronal projections to various brain regions including cerebral cortex, hippocampus or brain stem (Haas et al, 2008;Schneider et al, 2014a). Neuronal histamine activates postsynaptic H 1 R and H 2 R and regulates a multitude of behaviors and metabolic functions, e.g.…”

“…Neuronal histamine activates postsynaptic H 1 R and H 2 R and regulates a multitude of behaviors and metabolic functions, e.g. food intake, energy consumption, respiration, susceptibility to seizures, locomotor activity, cognition, pain perception, circadian rhythm, sleep and wakefulness, arousal or emotional states (Schneider et al, 2014a). The release of neuronal histamine is controlled by a negative feedback, which is mediated by the presynaptic Ga i/o -coupled H 3 R (Haas et al, 2008;Schneider et al, 2014b).…”

Effects of microinjection of histamine into the anterior cingulate cortex on pain-related behaviors induced by formalin in rats

“…Histamine, as a biogenic amine, found throughout the body in neuronal and non-neuronal sources, can modify pain transmission in the peripheral organs, spinal cord and brain by action at its H 1 , H 2 , H 3 and H 4 receptors [1][2][3]. At the supraspinal level, the involvement of histamine H 1 , H 2 and H 3 receptors have been reported in the antinociceptive effects induced by microinjection of histamine into the brain regions such as periaqueductal gray (PAG), raphe nucleus (RN), locus coeruleus (LC), dorsal hippocampus (DH), dentate gyrus (DG) and primary somatosensory cortex (PSC) [4][5][6][7][8].…”