Pharmacological diversity between native human 5‐HT 1B and 5‐HT 1D receptors sited on different neurons and involved in different functions

The releases of [ 3 H]5‐hydroxytryptamine ([ 3 H]5‐HT) and of endogenous glutamic acid and their modulation through presynaptic h5‐HT 1B autoreceptors and h5‐HT 1D 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 m M )‐evoked overflow of [ 3 H]5‐HT was antagonized by the 5‐HT 1B /5‐HT 1D receptor ligand GR 127935, which was ineffective on its own; this drug was previously found to behave as a full agonist at the h5‐HT 1D heteroreceptor regulating glutamate release. The recently proposed selective h5‐HT 1B 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 μ M , was unable to interact with the h5‐HT 1D heteroreceptor. The inhibitory effect of 5‐HT on the K + ‐evoked overflow of glutamate was antagonized by the h5‐HT 1D receptor ligand BRL‐15572; added in the absence of 5‐HT the compound was without effect. BRL‐15572 (1 μ M ) was unable to modify the effect of 5‐HT at the autoreceptor regulating [ 3 H]5‐HT release. The selective 5‐HT 1A receptor antagonist (+)‐WAY 100135, previously found to be an agonist at the h5‐HT 1D heteroreceptor regulating glutamate release, could not interact with the h5‐HT 1B autoreceptor when added at 1 μ M . It is concluded that native h5‐HT 1B and h5‐HT 1D receptors exhibit a hitherto unexpected pharmacological diversity.British Journal of Pharmacology (1999) 126 , 607–612; doi: 10.1038/sj.bjp.0702336