The role of the 5-HT 1D 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-HT 1B 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-HT 1D receptor-preferring antagonists, 1-[2-[4-(6-fluoro-1 H-indol-3-yl)-3,6-dihydro-2 H-pyridin-1-yl]-ethyl]-3-pyridin-4-yl-methyl-tetrahydro-pyrimidin-2-one (LY367642), ( R)-1-[2-(4-(6-fluoro-1 H-indol-3-yl-)-3,6-dihydro-1(2 H)-pyridinyl)ethyl]-3,4-dihydro-1 H-2-benzopyran-6-carboxamide (LY456219), ( S)-1-[2-(4-(6-fluoro-1 H-indol-3-yl-)-3,6-dihydro-1(2 H)-pyridinyl)ethyl]-3,4-dihydro-1 H-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 (EC 50 values=31–140 nM) in the same range as their affinities for the guinea pig 5-HT 1D receptor ( K i values=100–333 nM). The selective 5-HT 1D receptor agonist, R-2-(4-fluoro-phenyl)-2-[1-[3-(5-[1,2,4]triazol-4-yl-1 H-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-HT 1D 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-HT 1D receptor, like the 5-HT 1B receptor, may be a presynaptic autoreceptor in the guinea pig.