Pharmacological diversity between native human 5-HT1B and 5-HT1D receptors sited on different neurons and involved in different functions.
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 microM, 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 microM) 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 microM. It is concluded that native h5-HT1B and h5-HT1D receptors exhibit a hitherto unexpected pharmacological diversity.
Marcoli
M
M
Dipartimento di Medicina Sperimentale, Sezione di Farmacologia e Tossicologia, Università di Genova, Italy.
Maura
G
G
Munari
C
C
Ruelle
A
A
Raiteri
M
M
D000328:Adult; D000368:Aged; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010881:Piperidones / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014316:Tritium
D001713:Biphenyl Compounds; C470302:HTR1B protein, human; D010069:Oxadiazoles; D010879:Piperazines; D010881:Piperidones; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; C108518:SB 22489G; D012702:Serotonin Antagonists; D013141:Spiro Compounds; D014316:Tritium; C081293:WAY 100135; C090701:GR 127935; D012701:Serotonin; D018698:Glutamic Acid; D011189:Potassium Chloride; C108532:BRL 15572