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

1 The releases of [H-3]S-hydroxytryptamine ([H-3]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. 2 The inhibition by 5-HT of the K+ (15 mM)-evoked overflow of [H-3]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. 3 The recently proposed selective h5-HT1B receptor ligand SE-224289 also prevented the effect of 5-HT at the autoreceptor, being inactive on its own; in contrast, SB-224289, at 1 mu M, was unable to interact with the h5-HT1D heteroreceptor. 4 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 mu M) was unable to modify the effect of 5-HT at the autoreceptor regulating [H-3]S-HT release. 5 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 I mu M. 6 It is concluded that native h5-HT1B and h5-HT1D receptors exhibit a hitherto unexpected pharmacological diversity.