Cellular distribution of the histamine H3 receptor in the basal ganglia: Functional modulation of dopamine and glutamate neurotransmission

Abstract 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.