Molecular pharmacology of 5-HT 1 and 5-HT 2 recognition sites in rat and pig brain membranes: Radioligand binding studies with [ 3H]5-HT, [ 3H]8-OH-DPAT, (−)[ 125I]iodocyanopindolol, [ 3H]mesulergine and [ 3H]Ketanserin

Abstract

The pharmacological characteristics of the binding of [ 3H]8-OH-DPAT ([ 3H]8-hydroxy-2(di-n-propylamino)tetralin, [ 125I]CYP ((−)[ 125I]iodocyanopindolol) (in the presence of 30 μM (−)isoprenaline) and [ 3H]mesulergine to 5-HT 1 recognition sites were studied in rat and pig brain membranes. [ 3H]8-OH-DPAT bound in rat and pig cortex to the 5-HT 1A recognition site characterized by high affinity for 5-CT (5-carboxamido-tryptamine), 8-OH-DPAT, 5-HT (5-hydroxytryptamine, serotonin) and low affinity for pirenperone, ketanserin and mesulergine. [ 125I]CYP bound in rat but not in pig cortex to the 5-HT 1B site which shows high affinity for (−)21-009 (4[3-ter-butyl-amino-2-hydroxy-propoxy]indol-2-carbonic acid isopropyl ester), (±)ICYP (3-I-cyanopindolol), 5-HT, RU 24969 (5-methoxy-3-[1,2,3,6-tetrahydropiridon-4-yl]1H-indole) and low affinity for 8-OH-DPAT, mesulergine and pirenperone. [ 3H]Mesulergine bound in pig choroid plexus and in rat cortex (besides binding to 5-HT 2 sites in rat cortex) to the 5-HT 1C recognition site characterized by high affinity for metergoline, mesulergine, 5-HT and methergine and low affinity for (−)21-009, ICYP, 8-OH-DPAT and spiroperidol. The pharmacological profile of 5-HT 1A sites in rat and pig cortex appears to be identical: 5-HT 1C sites in pig choroid plexus and rat cortex show no differences. In contrast, it was not possible to label 5-HT 1B sites with [ 125I]CYP in pig brain membranes indicating that like 5-HT 2 receptors, 5-HT 1 recognition sites show species differences. The pharmacological profiles of the three 5-HT 1 recognition sites are clearly different from one another. Furthermore, the pharmacological profile of each individual 5-HT 1 recognition site is also different from that of the 5-HT 2 receptors labelled with [ 3H]ketanserin in rat cortex membranes although some similarities exist between 5-HT 2 and 5-HT 1C sites. Finally, the β-adrenoceptor antagonist (−)21-009 which has different affinities for 5-HT 1A, 5-HT 1B and 5-HT 1C recognition sites, yielded triphasic competetion curves for [ 3H]5-HT binding in rat cortex membranes providing evidence that [ 3H]5-HT labels three distinct 5-HT 1 sites in these membranes.