Histamine H 3 Receptors Decrease Dopamine Release in the Ventral Striatum by Reducing the Activity of Striatal Cholinergic Interneurons

Abstract

Histamine H receptors are widely distributed G-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 H 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 H 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 H receptors affected optogenetically evoked dopamine overflow, indicating that direct H-modulation of dopaminergic axons is unlikely. Next, we used qPCR and confirmed the expression of histamine H receptor mRNA in cholinergic interneurons, both in ventral and dorsal striatum. Activation of H 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 H 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.

Cholinergic modulation of striatal microcircuits

“…Similarly, histamine‐containing afferents from the hypothalamic tuberomamillary nucleus (Bolam & Ellender, ) depolarize ChIs by the activation of GPCR histamine receptor type 1 (H 1 ) (Bell et al., ). In nucleus accumbens, the activation of ChI H 3 receptors decreases their spontaneous activity, but this effect can only be observed in accumbens since striatum does not seem to express this histamine receptor subtype (Varaschin et al., ). The purine nucleoside, adenosine, is released by neurons and glia.…”

Abnormal behavior, striatal dopamine turnover and opioid peptide gene expression in histamine‐deficient mice

“…Histamine may indirectly modulate dopamine release through Hrh1 and Hrh3 and regulate dopamine‐dependent signaling in medium spiny neurons via Hrh3 . The absence of the endogenous ligand for histamine receptors in Hdc KO mice may therefore lead to increased striatal dopamine release, although the exact mechanism has not been revealed yet.…”

“…Striatal Hrh3 receptors may be a link between the hyperactive striatal dopaminergic system and tic‐like behavior . Hrh3 receptor activation differentially regulates intracellular signaling in medium spiny neurons of direct (expressing dopamine 1 receptors, D1‐MSN) and indirect (expressing dopamine 2 receptors, D2‐MSN) pathways and decreases dopamine release in ventral, but not dorsal striatum . Mice lacking Hrh3 receptors show abnormal prepulse inhibition and dopamine receptor signaling in striatum .…”

Central histaminergic signalling, neural excitability and epilepsy

“…The inhibitory role of H 3 receptors in regulating neurotransmitter release may also work indirectly. For instance, H 3 receptors activation decreased cholinergic interneuron activity, leading to the decline of dopamine release in ventral striatum dopaminergic neurons (Varaschin et al, 2018).…”