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

1. 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. 2. The inhibition by 5-HT of the K(+) (15 mM)-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. 3. 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 μM, was unable to interact with the h5-HT(1D) heteroreceptor. 4. 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 μM) was unable to modify the effect of 5-HT at the autoreceptor regulating [(3)H]5-HT release. 5. 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 μM. 6. It is concluded that native h5-HT(1B) and h5-HT(1D) receptors exhibit a hitherto unexpected pharmacological diversity