5-HT1A-receptors mediate stimulation of adenylate cyclase in rat hippocampus

Abstract

Serotonin (5-HT) stimulated adenylate cyclase activity in homogenates of rat hippocampus. This effect was pharmacologically characterised with a series of agonists and antagonists of various structural classes. These compounds where also tested in radioligand binding studies using selective ligands for the various subtypes of 5-HT₁ and 5-HT₂ receptors. 5-HT_1A, 5-HT_1B and 5-HT_1C recognition sites were labelled with [³H]8-OH-DPAT ([³H]8-hydroxy-2-(di-n-propylamino)-tetralin) in pig cortex membranes, [¹²⁵I]CYP([¹²⁵I]iodocyanopindolol) in rat cortex and [³H]mesulergine in pig choroid plexus membranes, respectively. The rank order of potency of 13 agonists stimulating adenylate cyclase activity in homogenates of rat hippocampus was in good agreement with the rank order of affinity of these agonists for the 5-HT_1A binding site: N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT)>5-carboxamidotryptamine (5-CT)>8-OH-DPAT>5-HT> 5-methoxytryptamine (5-OCH₃T)>d-LSD>5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969)>α-methylserotonin (α-CH₃-5-HT)>dopamine>2-methylserotonin (2-CH₃-5-HT). The correlation between the respective potencies and affinities of these agonists was r=0.934, P1B, 5-HT_1C or 5-HT₂ binding sites. r=0.381–0.108, PM receptors (ICS 205-930), 5-HT₂-receptors (ketanserin) and 5-HT_1C-receptors (mesulergine) antagonised the 5-HT stimulated adenylate cyclase activity only at very high concentrations. In contrast, spiperone and metitepin were potent antagonists of the effect of 5-CT and 5-HT on adenylate cyclase. The use of these selective antagonists allowed to exclude the possibility that 5-HT stimulates adenylate cyclase activity in rat hippocampus through D-1, 5-HT_M, 5-HT₂ or 5-HT_1C receptors. These data support the concept that 5-HT stimulated adenylate cyclase activity in rat hippocampus is mediated by a 5-HT_1A receptor.