The role of cortical and hypothalamic histamine‐3 receptors in the modulation of central histamine neurotransmission: an in vivo electrophysiology and microdialysis study

Abstract

The current study aimed to investigate the effect of histamine-3 (H(3)) receptors, expressed in the tuberomammillary nucleus (TMN) of the hypothalamus and in the prefrontal cortex (PFC), on histamine neurotransmission in the rat brain. The firing activity of histamine neurons in the TMN was measured using in vivo extracellular single-unit electrophysiology, under propofol anesthesia. Extracellular histamine levels were determined using the dual (PFC and TMN) probe microdialysis, in freely-moving animals. Histamine levels in dialysates were determined using high-performance liquid chromatography (HPLC) and fluorescence detection. It was found that systemic administration of the selective H(3)-agonist, immepip, decreases, and the reverse H(3) /H(4)-agonist, thioperamide, increases the firing activity of histamine neurons in the TMN and the release of histamine in TMN and PFC. Local perfusion of immepip into the TMN increased, and thioperamide decreased, histamine levels in the TMN but not in the PFC. Local perfusion of immepip into the PFC, however, decreased extracellular histamine levels in both TMN and PFC. It can be concluded that brain H(3) receptors, and especially those expressed in the PFC, play an important role in the autoregulation of histamine neurotransmission. It is possible that H(3) receptors in the PFC are expressed on pyramidal neurons projecting to the TMN, and activation of these receptors diminishes glutamate excitatory input from PFC to the TMN. As the brain histamine system has a role in pathophysiology of psychotic, affective, cognitive, sleep and eating disorders, H(3) receptors are potential targets for future CNS medications.

Histaminergic modulation in Tourette syndrome

“…Histamine acts through four receptors (H1-H4) and actively regulates arousal, feeding, learning and memory processes [56,57]. H1 and H2 receptors are expressed throughout the central nervous system, H3 receptors are limited to the brain, and H4 receptors are primarily located in the immune system, with limited action on the brain [58,59]. Specifically, H3 receptors are found in high concentrations throughout the cortex, hippocampus and striatum [54], the latter of which has been strongly associated with TS pathophysiology.…”

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“…5 Blockade of human H 3 autoreceptor by thioperamide evokes the increase of the neuronal histamine release. 15 In peripheral tissues, H 3 receptors are expressed in neuro-endocrine organs and regulate their functions. For example, the activation of H 3 receptors inhibited the release of adrenocorticotropic hormone and prolactin from the pituitary gland and of histamine from enterochromaffin-like cells and histamine also release from cerebral neurones in rat cortex.…”

Purinergic regulation of brain catecholamine neurotransmission: In vivo electrophysiology and microdialysis study in rats

“…Extracellular single-unit in vivo electrophysiological recordings were performed, as previously described (Dremencov et al 2007a(Dremencov et al , 2007b(Dremencov et al , 2009(Dremencov et al , 2017Flik et al 2011). Surgical anesthesia was maintained using propofol (20%) continuously administered intravenously (i.v., via a catheter placed in the lateral tail vein) at a rate 20 µl/min (for 300 g rat) by a microperfusion pump (CMA 102, Stockholm, Sweden).…”

“…Microdialysis experiments were performed as previously described (Dremencov et al 2004a(Dremencov et al , 2005Westerink and Cremers 2007;Allers et al 2010;Cremers et al 2010;Bloms-Funke et al 2011;Flik et al 2011Flik et al , 2015Yamada et al 2013;Visser et al 2015). I-shaped probes (Hospal AN 69 membrane, Brainlink, Groningen, the Netherlands) were inserted in the PFC (5.0 mm dorsal from the brain surface, 4 mm exposed surface probe) or NAcc (7.9 mm dorsal from the brain surface, 1.5 mm exposed surface probe); experiments were carried out 24-48 hours after surgery.…”

“…The flow was mixed (postcolumn) with a makeup flow of 0.15 ml/minute of the mobile phase (acetonitrile with 0.1% formic acid in ultrapure water with 0.1% formic acid), and directed to mass spectrometer (API 4000, Applied Biosystems, Foster City, CA, USA). Mass spectra were determined in multi-reaction mode (MRM) for 3-7 minutes (Dremencov et al 2004a(Dremencov et al , 2005Westerink and Cremers 2007;Allers et al 2010;Cremers et al 2010;Bloms-Funke et al 2011;Flik et al 2011Flik et al , 2015Yamada et al 2013;Visser et al 2015).…”