Pharmacological diversity between native human 5‐HT1B and 5‐HT1D receptors sited on different neurons and involved in different functions

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Abstract
The releases of [3H]5‐hydroxytryptamine ([3H]5‐HT) and of endogenous glutamic acid and their modulation through presynaptic h5‐HT1B autoreceptors and h5‐HT1D heteroreceptors have been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery. The inhibition by 5‐HT of the K+ (15 mM)‐evoked overflow of [3H]5‐HT was antagonized by the 5‐HT1B/5‐HT1D receptor ligand GR 127935, which was ineffective on its own; this drug was previously found to behave as a full agonist at the h5‐HT1D heteroreceptor regulating glutamate release. The recently proposed selective h5‐HT1B receptor ligand SB‐224289 also prevented the effect of 5‐HT at the autoreceptor, being inactive on its own; in contrast, SB‐224289, at 1 μM, was unable to interact with the h5‐HT1D heteroreceptor. The inhibitory effect of 5‐HT on the K+‐evoked overflow of glutamate was antagonized by the h5‐HT1D receptor ligand BRL‐15572; added in the absence of 5‐HT the compound was without effect. BRL‐15572 (1 μM) was unable to modify the effect of 5‐HT at the autoreceptor regulating [3H]5‐HT release. The selective 5‐HT1A receptor antagonist (+)‐WAY 100135, previously found to be an agonist at the h5‐HT1D heteroreceptor regulating glutamate release, could not interact with the h5‐HT1B autoreceptor when added at 1 μM. It is concluded that native h5‐HT1B and h5‐HT1D receptors exhibit a hitherto unexpected pharmacological diversity. British Journal of Pharmacology (1999) 126, 607–612; doi:10.1038/sj.bjp.0702336