Pre-synaptic histamine H3 receptors regulate glutamate, but not GABA release in rat thalamus

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We have investigated the presence of histamine H3 receptors (H3Rs) on rat thalamic isolated nerve terminals (synaptosomes) and the effect of their activation on glutamate and GABA release. N-α-[methyl-3H]histamine ([3H]-NMHA) bound specifically to synaptosomal membranes with dissociation constant (Kd) 0.78 ± 0.20 nM and maximum binding (Bmax) 141 ± 12 fmol/mg protein. Inhibition of [3H]-NMHA binding by histamine and the H3R agonist immepip fit better to a two-site model, whereas for the H3R antagonist clobenpropit the best fit was to the one-site model. GTPγS (30 μM) decreased [3H]-NMHA binding by 55 ± 4% and made the histamine inhibition fit better to the one-site model. Immepip (30 nM) induced a modest, but significant increase (113 ± 2% of basal) in [35S]-GTPγS binding to synaptosomal membranes, an effect prevented by clobenpropit (1 μM) and by pre-treatment with pertussis toxin. In thalamus synaptosomes depolarisation-induced, Ca2+-dependent glutamate release was inhibited by histamine (1 μM, 25 ± 4% inhibition) and immepip (30 nM, 38 ± 5% reduction). These effects were reversed by clobenpropit (1 μM). Conversely, immepip (up to 1 μM) had no effect on depolarisation-evoked [3H]-GABA release. Extracellular synaptic responses were recorded in the thalamus ventrobasal complex by stimulating corticothalamic afferents. H3R activation reduced by 38 ± 7% the glutamate receptor-mediated field potentials (FPs), but increased the FP2/FP1 ratio (from 0.86 ± 0.03 to 1.38 ± 0.05) in a paired-pulse paradigm. Taken together, our results confirm the presence of H3Rs on thalamic nerve terminals and show that their activation modulates pre-synaptically glutamatergic, but not GABAergic neurotransmission.

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