title: The role of the 5-HT1D receptor as a presynaptic autoreceptor in the guinea pig.
abstract: The present study investigated the role of the 5-hydroxytryptamine (5-HT, serotonin)1D receptor as a presynaptic autoreceptor in the guinea pig. In keeping with the literature, the 5-HT1B selective antagonist, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine]oxalate (SB224289) potentiated [3H]5-HT outflow from pre-labelled slices of guinea pig cerebral cortex confirming its role as a presynaptic autoreceptor in this species. In addition, the 5-HT1D receptor-preferring antagonists, 1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl]-3-pyridin-4-yl-methyl-tetrahydro-pyrimidin-2-one (LY367642), (R)-1-[2-(4-(6-fluoro-1H-indol-3-yl-)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-3,4-dihydro-1H-2-benzopyran-6-carboxamide (LY456219), (S)-1-[2-(4-(6-fluoro-1H-indol-3-yl-)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-3,4-dihydro-1H-2-benzopyran-6-carboxamide (LY456220) and 1-[2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl]-3,3-dimethyl-1,2-dihydro-indol-2-one (LY310762), potentiated [3H]5-HT outflow from this preparation with potencies (EC50 values=31-140 nM) in the same range as their affinities for the guinea pig 5-HT1D receptor (Ki values=100-333 nM). The selective 5-HT1D receptor agonist, R-2-(4-fluoro-phenyl)-2-[1-[3-(5-[1,2,4]triazol-4-yl-1H-indol-3-yl)-propyl]-piperidin-4-ylamino]-ethanol dioxylate (L-772,405), inhibited [3H]5-HT outflow. In microdialysis studies, administration of either SB224289 or LY310762 at 10 mg/kg by the intraperitoneal (i.p.) route, potentiated the increase in extracellular 5-HT concentration produced by a maximally effective dose of the selective serotonin re-uptake inhibitor, fluoxetine (at 20 mg/kg i.p.). In addition, the 5-HT1D receptor-preferring antagonist and 5-HT transporter inhibitor, LY367642 (at 10 mg/kg i.p.), elevated extracellular 5-HT concentrations to a greater extent than a maximally effective dose of fluoxetine. It is concluded that the 5-HT1D receptor, like the 5-HT1B receptor, may be a presynaptic autoreceptor in the guinea pig.
authors.affiliation: Eli Lilly and Company Limited, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Pullar
authors.forename: John R
authors.initials: JR
authors.lastname: Boot
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Broadmore
authors.forename: Tina A
authors.initials: TA
authors.lastname: Eyre
authors.forename: Jane
authors.initials: J
authors.lastname: Cooper
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Sanger
authors.forename: Susan
authors.initials: S
authors.lastname: Wedley
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000502:physiology*; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D015283:Citalopram / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D006168:Guinea Pigs; D007031:Hypothalamus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000378:metabolism / Q000494:pharmacology; D017551:Microdialysis / Q000379:methods; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010881:Piperidones / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D044302:Receptor, Serotonin, 5-HT1B / Q000502:physiology; D044346:Receptor, Serotonin, 5-HT1D / Q000502:physiology; D017661:Receptors, Presynaptic / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D013045:Species Specificity; D013141:Spiro Compounds / Q000494:pharmacology; D013347:Subcellular Fractions / Q000737:chemistry / Q000473:pathology; D014230:Triazoles / Q000494:pharmacology; D014316:Tritium; D006113:United Kingdom
chemical_list: C496793:1-(2-(4-(4-fluoro-benzoyl)-piperidin-1-yl)-ethyl)-3,3-dimethyl-1,2-dihydro-indol-2-one; C496794:1-(2-(4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl)-ethyl)-3-pyridin-4-yl-methyl-tetrahydro-pyrimidin-2-one; D017660:Autoreceptors; D007211:Indoles; C402271:L 772405; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010880:Piperidines; D010881:Piperidones; D011743:Pyrimidines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D017661:Receptors, Presynaptic; C108518:SB 22489G; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D013141:Spiro Compounds; D014230:Triazoles; D005473:Fluoxetine; D015283:Citalopram; D014316:Tritium; D012701:Serotonin