Histamine H3 receptor activation inhibits glutamate release from rat striatal synaptosomes
Introduction
Histamine is a neuromodulator in the mammalian central nervous system, where it regulates, via both pre- and post-synaptic mechanisms, a variety of central responses and functions, such as wakefulness, feeding, drinking, the neuroendocrine system, body temperature, analgesia and motor activity (Wada et al., 1991, Schwartz et al., 1991, Onodera et al., 1994). The cell bodies of histaminergic neurones are located in the hypothalamus, from where they send diffuse projections to almost all brain regions (Wada et al., 1991). The actions of histamine are mediated by three well-defined receptors (H1, H2 and H3), characterised by their pharmacology and signal transduction mechanisms (Hill et al., 1997), although the molecular cloning of a fourth histamine receptor was recently reported (Oda et al., 2000, Liu et al., 2001, Nguyen et al., 2001, Zhu et al., 2001).
Histamine H3 receptors in the CNS appear to be present primarily on nerve terminals, where they regulate the release of histamine itself and of other neurotransmitters, such as acetylcholine, dopamine, noradrenaline and 5-hydroxytryptamine (Hill et al., 1997). In the striatum, which has the highest density of H3 receptors in both human and rat brain (Martı́nez-Mir et al., 1990, Cumming et al., 1991, Pollard et al., 1993), and in the substantia nigra pars reticulata, lesioning studies have shown that these receptors are present predominantly on the GABAergic projection neurones (Pollard et al., 1993, Ryu et al., 1994). In both the striatum and the substantia nigra H3 receptor activation leads to a marked and selective inhibition of the component of depolarisation-induced release of γ-aminobutyric acid (GABA) that is dependent on concomitant D1 receptor stimulation (Garcı́a et al., 1997, Arias-Montaño et al., 2001). This action in the basal ganglia, a group of subcortical nuclei intimately involved in the control of movement (Gerfen and Wilson, 1996), suggests that histamine might have an important role in disorders of motor control.
Nigrostriatal (dopaminergic) and corticostriatal (glutamatergic) pathways (Gerfen and Wilson, 1996) provide the major synaptic inputs to the striatum. We have recently shown that striatal synaptosomes are endowed with H3 receptors (Molina-Hernández et al., 2000a) and selective lesioning of dopaminergic neurones with 6-hydroxydopamine indicates that a minor fraction (∼20%) of presynaptic H3 receptors are located on nigrostriatal terminals, where they appear to modulate dopamine synthesis (Molina-Hernández et al., 2000a) and release (Schlicker et al., 1993). However, Doreulee et al. (2001) have recently shown that in rat striatum H3 receptor activation depresses the amplitude of extracellular field potentials evoked by corticostriatal stimulation. This suggests that a significant fraction of striatal H3 receptors could be located on corticostriatal afferents and regulate glutamate release. We provide here direct evidence for H3 receptor-mediated inhibition of glutamate release from isolated striatal nerve terminals. A preliminary account of some of these results has been presented to the Society for Neuroscience (Molina-Hernández et al., 2000b).
Section snippets
Animals
Male adult rats (250–300 g), Wistar strain, bred in the CINVESTAV facility, were used throughout. All efforts were made to minimise animal suffering, to use only as many animals were required for proper statistical analysis, and to seek alternatives to in vivo techniques.
Synaptosome preparation
Synaptosomes were prepared using a modification of the method of Gray and Whittaker (1962). Briefly, animals were killed by decapitation, the brain was rapidly removed from the skull and the striata were dissected out. Nuclei
Characteristics of release
Basal glutamate release was 0.46±0.04 nmol/mg protein (means±SEM from the combined values from 15 experiments). Addition of 4 mM 4-AP in the presence of 1.8 mM Ca2+ caused a significant increase in glutamate release and experiments in which Ca2+ ions were omitted from the incubation medium showed that 67±7% of 4-AP-stimulated release was Ca2+-dependent (7.1±0.4 nmol/mg protein). In subsequent experiments the Ca2+-independent component of 4-AP-stimulated release was subtracted from total
Discussion
Besides being located on histaminergic nerve terminals where they regulate the synthesis and release of histamine, H3 receptors are found as heteroreceptors that presynaptically inhibit the release of noradrenaline, 5-hydroxytryptamine, dopamine and GABA (Hill et al., 1997, Garcı́a et al., 1997, Arias-Montaño et al., 2001). The results presented herein provide direct support for a previous report (Doreulee et al., 2001) indicating that H3 receptor activation also inhibits glutamate release from
Acknowledgements
Supported by CINVESTAV and CONACYT (grant 28276N). A.M.H. is the recipient of a CONACYT predoctoral scholarship. We are thankful to Dr John Michael Young (University of Cambridge) for improving the manuscript.
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