title: Role of extracellular serotonin levels in the effect of 5-HT1B receptor blockade.
abstract: The release of serotonin (5-HT) at serotonergic nerve terminals is regulated by 5-HT(1B) autoreceptors. Several studies have reported that the effects of selective 5-HT reuptake inhibitors (SSRIs) on extracellular 5-HT are augmented by 5-HT(1B) receptor antagonists, whereas administration of these antagonists alone do not enhance 5-HT levels. It has been suggested that 5-HT(1B) receptors have low basal endogenous activity and therefore elevated endogenous 5-HT levels are needed to elicit an effect of 5-HT(1B) receptor antagonists. To test this hypothesis, different strategies were used to enhance 5-HT levels in the rat frontal cortex to assess the effects of locally applied NAS-181, a new selective 5-HT(1B) receptor antagonist. Blockade of 5-HT(1B) receptors with NAS-181 dose dependently augmented 5-HT levels when 5-HT levels were enhanced by a SSRI. No additional effect of NAS-181 on 5-HT output was found when 5-HT levels were enhanced by KCl depolarization-induced release or by preventing degradation of 5-HT with the monoamine oxidase inhibitor pargyline. In the presence of fluvoxamine, the increased 5-HT release evoked by KCl depolarization was augmented by NAS-181, supporting the idea that blockade of 5-HT transporters is necessary to measure an effect of 5-HT(1B) receptor blockade. In conclusion, the results provide circumstantial evidence that the effect of a 5-HT(1B) receptor antagonist depends on extracellular 5-HT levels, but strongly suggest that additional 5-HT reuptake inhibition is required to detect any effect of 5-HT(1B) receptor antagonist on 5-HT levels by in vivo microdialysis.
authors.affiliation: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Lotte
authors.initials: L
authors.lastname: de Groote
authors.forename: André A
authors.initials: AA
authors.lastname: Klompmakers
authors.forename: Berend
authors.initials: B
authors.lastname: Olivier
authors.forename: Herman G M
authors.initials: HG
authors.lastname: Westenberg
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000037:antagonists & inhibitors* / Q000502:physiology; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005110:Extracellular Space / Q000378:metabolism*; D016666:Fluvoxamine / Q000008:administration & dosage / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D010293:Pargyline / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013997:Time Factors
chemical_list: D017660:Autoreceptors; D001578:Benzopyrans; D016666:Fluvoxamine; D008996:Monoamine Oxidase Inhibitors; D009025:Morpholines; D010293:Pargyline; D011189:Potassium Chloride; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C112429:2-(((3-(morpholinylmethyl)-2H-chromen-8-yl)oxy)methyl)morpholine