title: Importance of h5-HT1B receptor selectivity for 5-HT terminal autoreceptor activity: an in vivo microdialysis study in the freely-moving guinea-pig.
abstract: The importance of h5-HT1B receptor selectivity for 5-HT terminal autoreceptor activity was investigated with the selective h5-HT1B receptor ligands SB 219085, SB 220272, SB 224289 and SB 216641. The studies employed measurement of compound affinity and efficacy in vitro and the measurement of extracellular 5-HT in the frontal cortex of the freely-moving guinea-pig using in vivo microdialysis. All compounds had high affinity and selectivity for the h5-HT1B receptor, with SB 224289 the most selective for h5-HT1B over h5-HT1D receptors. Compounds exhibited a range of efficacies at both receptors: SB 224289 and SB 219085 were inverse agonists, SB 220272 was an antagonist and SB 216641 was a partial agonist. SB 220272, SB 216641 and SB 224289 had no effect on extracellular 5-HT following systemic administration, however, SB 219085 produced a significant increase. The SB 219085-induced increase in extracellular 5-HT was attributed to the compounds non-specific releasing properties as it was also demonstrated to increase basal release of [3H]5-HT from pre-loaded guinea-pig cortical slices. The lack of effect of the above h5-HT1B receptor selective compounds and the decrease in extracellular 5-HT elicited by the non-selective compounds GR 127935, GR125743 and methiothepin suggest that antagonism of 5-HT1D receptors may mediate this decrease in 5-HT levels. It is plausible that blockade of 5-HT1D receptors increases 5-HT levels in the raphe, this activates 5-HTtA receptors which results in an overall decrease in terminal 5-HT release. Definitive proof now awaits elucidation of the action of a selective 5-HT1D receptor antagonist.
authors.affiliation: Department of Psychiatry Research, SmithKline Beecham Pharmaceuticals, Harlow, Essex, U.K. Claire_Roberts-1@sbphrd.com@inet
authors.forename: C
authors.initials: C
authors.lastname: Roberts
authors.forename: G W
authors.initials: GW
authors.lastname: Price
authors.forename: L
authors.initials: L
authors.lastname: Gaster
authors.forename: B J
authors.initials: BJ
authors.lastname: Jones
authors.forename: D N
authors.initials: DN
authors.lastname: Middlemiss
authors.forename: C
authors.initials: C
authors.lastname: Routledge
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000187:drug effects / Q000378:metabolism*; D001923:Brain Chemistry / Q000502:physiology; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004563:Electrochemistry; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D008024:Ligands; D008297:Male; D017551:Microdialysis; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*
chemical_list: D017660:Autoreceptors; D008024:Ligands; D011985:Receptors, Serotonin; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate)