Histamine H3 Receptors Decrease Dopamine Release in the Ventral Striatum by Reducing the Activity of Striatal Cholinergic Interneurons.
Neuroscience. 2018-04-01; 376: 188-203
DOI: 10.1016/j.neuroscience.2018.01.027
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Varaschin RK(1), Osterstock G(1), Ducrot C(1), Leino S(2), Bourque MJ(1), Prado MAM(3), Prado VF(3), Salminen O(2), Rannanpää Née Nuutinen S(2), Trudeau LE(4).
Author information:
(1)Department of Pharmacology and Physiology, Department of Neurosciences, School
of Medicine, CNS Research Group, Université de Montréal, Montréal, Québec H3T
1J4, Canada.
(2)Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University
of Helsinki, Helsinki FIN-00014, Finland.
(3)Molecular Medicine, Robarts Research Institute, Department of Physiology and
Pharmacology and Department of Anatomy & Cell Biology, University of Western
Ontario, London, Ontario N6A 5B7, Canada.
(4)Department of Pharmacology and Physiology, Department of Neurosciences, School
of Medicine, CNS Research Group, Université de Montréal, Montréal, Québec H3T
1J4, Canada. Electronic address: .
Histamine H3 receptors are widely distributed Gi-coupled receptors whose
activation reduces neuronal activity and inhibits release of numerous
neurotransmitters. Although these receptors are abundantly expressed in the
striatum, their modulatory role on activity-dependent dopamine release is not
well understood. Here, we observed that histamine H3 receptor activation
indirectly diminishes dopamine overflow in the ventral striatum by reducing
cholinergic interneuron activity. Acute brain slices from C57BL/6 or
channelrhodopsin-2-transfected DAT-cre mice were obtained, and dopamine
transients evoked either electrically or optogenetically were measured by
fast-scan cyclic voltammetry. The H3 agonist α-methylhistamine significantly
reduced electrically- evoked dopamine overflow, an effect blocked by the
nicotinic acetylcholine receptor antagonist dihydro-β-erythroidine, suggesting
involvement of cholinergic interneurons. None of the drug treatments targeting H3
receptors affected optogenetically evoked dopamine overflow, indicating that
direct H3-modulation of dopaminergic axons is unlikely. Next, we used qPCR and
confirmed the expression of histamine H3 receptor mRNA in cholinergic
interneurons, both in ventral and dorsal striatum. Activation of H3 receptors by
α-methylhistamine reduced spontaneous firing of cholinergic interneurons in the
ventral, but not in the dorsal striatum. Resting membrane potential and number of
spontaneous action potentials in ventral-striatal cholinergic interneurons were
significantly reduced by α-methylhistamine. Acetylcholine release from isolated
striatal synaptosomes, however, was not altered by α-methylhistamine. Together,
these results indicate that histamine H3 receptors are important modulators of
dopamine release, specifically in the ventral striatum, and that they do so by
decreasing the firing rate of cholinergic neurons and, consequently, reducing
cholinergic tone on dopaminergic axons.
Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.