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-HT1A, 5-HT1B and 5-HT1C 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-HT1A binding site: N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT) greater than 5-carboxamidotryptamine (5-CT) greater than 8-OH-DPAT greater than 5-HT greater than 5-methoxytryptamine (5-OCH3T) greater than d-LSD greater than 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969) greater than alpha-methylserotonin (alpha-CH3-5-HT) greater than dopamine greater than 2-methylserotonin (2-CH3-5-HT). The correlation between the respective potencies and affinities of these agonists was r = 0.934, P less than 0.001. There was no correlation between stimulation of adenylate cyclase activity by these agonists and their affinity for 5-HT1B, 5-HT1C or 5-HT2 binding sites. r = 0.381-0.108, P less than 0.20-0.73.(ABSTRACT TRUNCATED AT 250 WORDS)

Actions of 5‐hydroxytryptamine and 5‐HT1A receptor ligands on rat dorso‐lateral septal neurones in vitro

“…The concentration-response curves were parallel in nature and the maximum responses to the three agonists were similar. The rank order of potency of these three compounds (DP-5-CT> 8-OH-DPAT> 5-HT) is the same as that determined in radioligand binding experiments (pKD = 9.54, 8.74 and 8.51; Hoyer, 1991) and in second messenger tests (pECm = 7.40, 7.03 and 6.89, respectively; Markstein et al, 1986). Taken together, these findings support the conclusion that all three compounds were acting on the same population of receptors, namely 5-HTIA receptors.…”

“…This was achieved by measuring the effects of a number of novel synthetic 5-HTIA receptor agonists and antagonists on the neuronal membrane potential. 5-HT and the high affinity selective 5-HTIA receptor ligands, DP-5-CT (Markstein et al, 1986;Hoyer, 1991) and 8-OH-DPAT (Gozlan et al, 1983;Hoyer, 1991) hyperpolarized the membrane potential in a concentrationdependent manner. The concentration-response curves were parallel in nature and the maximum responses to the three agonists were similar.…”

“…It was also noted that the maximum response to buspirone (7.0 ± 1.1 mV, n = 4) was significantly smaller than that to 8-OH-DPAT (13.8 ± 0.6 mV, n = 8; P<0.05) or 5-HT (I 5.9 + 0.9 mV, n = 19; P< 0.001). DP-5-CT (0.001-1 JAM), a potent and selective 5-HTIA receptor agonist, induced a hyperpolarization which was, like 8-OH-DPAT, slow in onset and poorly reversible (Figure 3c; Markstein et al, 1986). In 4 cells, 4-5 concentrations of DP-5-CT were applied in a cumulative manner and the calculated EC50 was 17.3 ± 3.0 nm.…”

Further characterization of the 5‐HT receptor mediating vascular relaxation and elevation of cyclic AMP in porcine isolated vena cava

“…Surprisingly, 2-methyl-5-HT (an agonist normally considered to be selective for 5-HT3 receptors) produced some relaxation of preparations contracted with a-methyl-5-HT, albeit at concentrations one A number of groups have described effects of 5-HT and 5-CT on adenylate cyclase activity in brain tissues. Both stimulant (Barbaccia et al, 1983;Shenker et al, 1983;1987;Markstein et al, 1986) and inhibitory (DeVivo & Maayani, 1986;Weiss et al, 1986;Hoyer & Schoeffter, 1988) effects have been described and assigned to various types of 5-HT1 binding site (for review see Roth & Chuang, 1987 (Fozard, 1987), were similarly devoid of appreciable activity in our study. The possibility that 5-HT1c or 5-HT1D sites could mediate the effects of 5-HT, as might be suggested by the antagonist potencies of mesulergine and metergoline (Table 2), is excluded on the basis of the high affinity of spiperone for the porcine vena cava receptor as compared to its low affinity at 5-HT1c and 5-HTlD binding sites (Heuring & Peroutka, 1987).…”

The guinea‐pig ileum preparation as a model for 5‐HT1A receptors: anomalous effects with RS‐30199–193

“…These assays include inhibition (Bockaert et al, 1987) or stimulation (Markstein et al, 1986) of adenylate cyclase activity in hippocampal neurones, or inhibition of electrical spike activity in the same tissue (Rowan & Anwyl, 1987). We have therefore extended the functional assay proposed by Fozard & Kilbinger (1985) and Mir et al (1988) which measures inhibition of responses to field stimulation in the guinea-pig ileum preparation.…”