Increased Sensitivity of Mice Lacking Extrasynaptic delta-Containing GABA(A) Receptors to Histamine Receptor 3 Antagonists

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Abdurakhmanova , S , Grotell , M , Kauhanen , J , Linden , A-M , Korpi , E R & Panula , P 2020 , ' Increased Sensitivity of Mice Lacking Extrasynaptic delta-Containing GABA(A) Receptors to Histamine Receptor 3 Antagonists ' , Frontiers in Pharmacology , vol. 11 , 594 . https://doi.org/10.3389/fphar.2020.00594

Title: Increased Sensitivity of Mice Lacking Extrasynaptic delta-Containing GABA(A) Receptors to Histamine Receptor 3 Antagonists
Author: Abdurakhmanova, Shamsiiat; Grotell, Milo; Kauhanen, Jenna; Linden, Anni-Maija; Korpi, Esa R.; Panula, Pertti
Contributor: University of Helsinki, Department of Anatomy
University of Helsinki, Medicum
University of Helsinki, Anni-Maija Linden / Principal Investigator
University of Helsinki, Esa Risto Korpi / Principal Investigator
University of Helsinki, Helsinki In Vivo Animal Imaging Platform (HAIP)
Date: 2020-05-06
Language: eng
Number of pages: 13
Belongs to series: Frontiers in Pharmacology
ISSN: 1663-9812
URI: http://hdl.handle.net/10138/316277
Abstract: Histamine/gamma-aminobutyric acid (GABA) neurons of posterior hypothalamus send wide projections to many brain areas and participate in stabilizing the wake state. Recent research has suggested that GABA released from the histamine/GABA neurons acts on extrasynaptic GABA(A) receptors and balances the excitatory effect of histamine. In the current study, we show the presence of vesicular GABA transporter mRNA in a majority of quantified hypothalamic histaminergic neurons, which suggest vesicular release of GABA. As histamine/GABA neurons form conventional synapses infrequently, it is possible that GABA released from these neurons diffuses to target areas by volume transmission and acts on extrasynaptic GABA receptors. To investigate this hypothesis, mice lacking extrasynaptic GABA(A) receptor delta subunit (Gabrd KO) were used. A pharmacological approach was employed to activate histamine/GABA neurons and induce histamine and presumably, GABA, release. Control and Gabrd KO mice were treated with histamine receptor 3 (Hrh3) inverse agonists ciproxifan and pitolisant, which block Hrh3 autoreceptors on histamine/GABA neurons and histamine-dependently promote wakefulness. Low doses of ciproxifan (1 mg/kg) and pitolisant (5 mg/kg) reduced locomotion in Gabrd KO, but not in WT mice. EEG recording showed that Gabrd KO mice were also more sensitive to the wake-promoting effect of ciproxifan (3 mg/kg) than control mice. Low frequency delta waves, associated with NREM sleep, were significantly suppressed in Gabrd KO mice compared with the WT group. Ciproxifan-induced wakefulness was blocked by histamine synthesis inhibitor alpha-fluoromethylhistidine (alpha FMH). The findings indicate that both histamine and GABA, released from histamine/GABA neurons, are involved in regulation of brain arousal states and delta-containing subunit GABA(A) receptors are involved in mediating GABA response.
Subject: extrasynaptic GABAA receptor
GABAA delta subunit
Gabrd KO mice
Electroencephalogram
histamine
GABA
ciproxifan
pitolisant
H-3 RECEPTOR
HISTIDINE-DECARBOXYLASE
ALPHA-FLUOROMETHYLHISTIDINE
H3 RECEPTOR
RELEASE
BRAIN
RAT
SUBUNIT
MOUSE
FOREBRAIN
3111 Biomedicine
317 Pharmacy
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