Pharmacological characterisation of 5-HT receptors positively coupled to adenylyl cyclase in the rat hippocampus

Abstract

The pharmacological properties of 5-hydroxytryptamine (5-HT) receptors positively coupled to adenylyl cyclase in the rat hippocampus were investigated using selective agonists and antagonists. 5-HT (0.008-125 microM) stimulated cyclic AMP formation in homogenates of rat hippocampus in a concentration-dependent manner. The maximal increase in cyclic AMP formation occurred at 1 microM (141+/-6%) and the half-maximal effect (EC50) at 50+/-22 nM. Cyclic AMP accumulation induced by 1 microM 5-HT was partly inhibited by the selective 5-HT1A receptor antagonist WAY 100,635 (1 microM), the selective 5-HT4 receptor antagonist SB 203,186 (1 microM), and the 5-HT2A/c/ 5-HT7 receptor antagonist mesulergine (25 microM). WAY 100,635, SB 203,186 and mesulergine inhibited the effect of 5-HT (1 microM) by 47%, 33% and 49%, respectively. The combination of WAY 100,635 (1 microM) with SB 203,186 (1 microM) or mesulergine (25 microM) resulted in stronger inhibition than with each antagonist alone, and the combination of all three antagonists produced almost total blockade (95%) of 5-HT-induced cyclic AMP accumulation. 5-Carboxamidotryptamine (5-CT; 0.008-125 microM), a 5-HT1/5-HT7 receptor agonist, and SDZ 216-454 (0.008-125 microM), a selective 5-HT4 receptor agonist, concentration-dependently stimulated cyclic AMP formation, but the maximal effect of each agonist was smaller than that of 5-HT alone. SDZ 216-454 (5 microM) and 5-CT (5 microM) in combination stimulated cyclic AMP formation in an additive manner. 8-OH-PIPAT and 8-OH-DPAT, two selective 5-HT1A agonists, produced a small but significant increase in cyclic AMP formation at concentrations above 0.04 microM and 10 microM, respectively. These findings suggest that at least three 5-HT receptor subtypes, i.e. 5-HT1A, 5-HT7 and 5-HT4 receptors, are involved in mediating 5-HT-induced cyclic AMP formation in rat hippocampus.

Reconsideration of 5-Hydroxytryptamine (5-HT)7Receptor Distribution Using [3H]5-Carboxamidotryptamine and [3H]8-Hydroxy-2-(di-n-propylamino)tetraline: Analysis in Brain of 5-HT1AKnockout and 5-HT1A/1BDouble-Knockout Mice

“…In Waeber and Moskowitz's (1995) study the masking of 5-HT 1A binding sites by 100 nM 8-OH-DPAT is likely to block a large fraction of the 5-HT 7 receptor binding sites because of the affinity of this compound for the 5-HT 7 receptor Plassat et al, 1993;Ruat et al, 1993;Shen et al, 1993). In Gustafson et al (1996), the concentration of pindolol (160 nM (Markstein et al, 1999;Thomas et al, 1999) demonstrated an interaction of 5-HT 1A and 5-HT 7 receptors in hippocampus. The 5-HT 7 receptor-mediated stimulation of adenylyl cyclase activity by 5-CT seems to be augmented by a mechanism involving 5-HT 1A receptor activation.…”

Regulation of Surface Localization of the Small Conductance Ca2+-activated Potassium Channel, Sk2, through Direct Phosphorylation by cAMP-dependent Protein Kinase

“…Moreover, functional studies in rat jaw-closing spinal motor neurons have coupled activation of the metabotrophic 5-HT 1A receptor to down-regulation of the apamin-sensitive I mAHP (45). The exact pathway mediating this effect in spinal motor neurons is unknown, but activation of the 5-HT 1A receptor induces downstream cAMP accumulation and PKA activation (46). Therefore, activation of 5-HT 1A receptors in spinal motor neurons may result in direct phosphorylation of the SK2 subunit and modulation of the I mAHP .…”

Ras-dependent ERK Activation by the Human Gs-coupled Serotonin Receptors 5-HT4(b) and 5-HT7(a)

“…In Aplysia, activation of mitogen-activated protein kinases by serotonin is implicated in memory formation and occurs through a G scoupled 5-HT receptor (32,33). In mammalian brain, 5-HT 4 and 5-HT 7 receptors are both found in the hippocampus (36,37), and 5-HT 7 receptors were recently shown to activate ERKs in cultured hippocampal neurons (35). The importance of ERK activation for the involvement of these receptors in learning and memory (38) remains to be determined.…”

“…In cultured rat hippocampal neurons, 5-HT activated ERK1/2 through 5-HT 7 receptors, but the mechanism was not characterized (35). In mammalian brain, both 5-HT 4 and 5-HT 7 receptors are found in the hippocampus (36,37), and these receptors are both believed to be important in learning and memory (38). Thus, there is a need to determine whether 5-HT 4 and 5-HT 7 receptors can activate ERK, as well as the mechanism for such activation.…”