Cellular distribution of the histamine H 3 receptor in the basal ganglia: Functional modulation of dopamine and glutamate neurotransmission Marta Gonza ´ lez-Sepu ´ lveda a , Santi Rosell a,1 , Hanne M. Hoffmann b,1 , M del Mar Castillo-Ruiz a , Virginie Mignon c , David Moreno-Delgado a , Michel Vignes b , Jorge Dı ´az c , Josefa Sabria ´ a , Jordi Ortiz a, * a Neuroscience Institute and Department of Biochemistry and Molecular Biology, School of Medicine, Universitat Autonoma de Barcelona, Bellaterra, Spain b Oxidative Stress and Neuroprotection, IBMM, CNRS UMR-5247, University of Montpellier II, Place E. Bataillon, 34095 Montpellier Cedex 5, France c Universite ´ Paris Descartes and INSERM U-894, Neurobiologie et Pharmacologie Mole ´culaire, Paris, France Introduction Histamine is involved in a variety of brain functions such as the sleep–wake cycle, attention, learning, memory and the control of food intake and locomotion [1,2] through its interaction with four identified G-protein coupled receptors. Three of them (H 1 to H 3 ) are widely distributed in the central nervous system while the H 4 receptor is expressed mostly in bone marrow and leukocytes, displaying very low levels in brain [3,4]. The histamine H 3 receptor (H 3 R) was initially described as an autoreceptor controlling histamine release and synthesis in histaminergic terminals of the central nervous system [5,6]. Later, its heteroreceptor role was demonstrated as it also modulates the release of other neurotransmitters including serotonin [7], norepinephrine [8], dopamine [9], glutamate [10] and GABA [11] in brain samples. Many human and rat H 3 R mRNA isoforms are generated by differential splicing [12]. In the rat, four isoforms are functionally active: H 3(445) , H 3(413) , H 3(410) , H 3(397) . H 3(413) has been suggested to be the autoreceptor of histaminergic neurons [13]. The H 3 R isoforms have a heterogenous expression level in cerebral structures [14] being highly expressed in cortex, thalamus and caudate–putamen [15]. This regional localization matches the relative distribution of histaminergic projections arising from the tuberomammillary nucleus. In addition, radioligand binding studies in rodents show high H 3 R levels in olfactory nucleus, cortex, substantia nigra pars reticulata (SNr), amygdala, thalamus and hypothalamus, specially in tuberomammillary nucleus, with the highest density in striatum and nucleus accumbens [16]. The rat striatum is the main input structure of the basal ganglia involved in sensory-motor behavioural coordination. It can be Basal Ganglia 3 (2013) 109–121 A R T I C L E I N F O Article history: Received 3 October 2012 Received in revised form 10 December 2012 Accepted 10 December 2012 Keywords: Histamine H 3 receptor Colocalization Dopamine Electrophysiology A B S T R A C T Histamine H 3 receptors (H 3 R) are widely expressed in the brain where they participate in sleep–wake cycle and cognition among other functions. Despite their high expression in some regions of the basal ganglia, their functional role in this forebrain neural network remains unclear. The present findings provide in situ hybridization and immunohistochemical evidence for H 3 R expression in several neuronal populations of the rat basal ganglia but not in astrocytes (glial fibrillary acidic protein immunoreactive cells). We demonstrate the presence of H 3 R mRNA and protein in dopaminergic neurons (tyrosine hydroxylase positive) of the ventral tegmental area and substantia nigra. In the dorsal and ventral (nucleus accumbens) striatal complex we show H 3 R immunoreactivity in cholinergic (choline acetyltransferase immunoreactive) and GABAergic neurons (substance P, proenkephalin or dopamine D 1 receptor positive) as well as in corticostriatal terminals (VGLUT1-immunoreactive). Double-labelling experiments in the medial prefrontal cortex show that H 3 R is expressed in D 1 R-positive interneurons and VGLUT1-positive corticostriatal output neurons. Our functional experiments confirm that H 3 R ligands modulate dopamine synthesis and the probability of glutamate release in the striatum from cortico-striatal afferents. The presence of H 3 R in such different neuronal populations and its involvement in the control of striatal dopaminergic and glutamatergic transmission ascribes a complex role to H 3 R in the function of the basal ganglia neural network. ß 2012 Elsevier GmbH. All rights reserved. Abbreviations: Acb, nucleus accumbens; D1R, dopamine receptor 1; H3R, histamine receptor 3; PE, proenkephalin; SNc, substance nigra pars compacta; SNr, substance nigra pars reticulata; SP, substance P; SSC, sodium saline citrate; TBS, 50 mM tris buffer saline pH 7.6; TSA, tyramide signal amplification; VGLUT1, vesicular glutamate transporter 1; VTA, ventral tegmental area. * Corresponding author at: Neuroscience Institute and Department of Biochem- istry and Molecular Biology, School of Medicine, Room M2-113, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain. Tel.: +34 935814827; fax: +34 935811573. E-mail address: jordi.ortiz@uab.es (J. Ortiz). 1 These authors contributed equally to this paper. Contents lists available at SciVerse ScienceDirect Basal Ganglia jo u rn al h om ep age: ww w.els evier.c o m/lo c ate/b aga 2210-5336/$ – see front matter ß 2012 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.baga.2012.12.001