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 μM) stimulated cyclic AMP formation in homogenates of rat hippocampus in a concentration-dependent manner. The maximal increase in cyclic AMP formation occurred at 1 μM (141 ± 6%) and the half-maximal effect (EC₅₀) at 50 ± 22 nM. Cyclic AMP accumulation induced by 1 μM 5-HT was partly inhibited by the selective 5-HT_1A receptor antagonist WAY 100,635 (1 μM), the selective 5-HT₄ receptor antagonist SB 203,186 (1 μM), and the 5-HT_2A/C/ 5-HT₇ receptor antagonist mesulergine (25 μM). WAY 100,635, SB 203,186 and mesulergine inhibited the effect of 5-HT (1 μM) by 47%, 33% and 49%, respectively. The combination of WAY 100,635 (1 μM) with SB 203,186 (1 μM) or mesulergine (25 μM) 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 μM), a 5-HT₁/5-HT₇ receptor agonist, and SDZ 216–454 (0.008– 125 μM), 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 μM) and 5-CT (5 μM) in combination stimulated cyclic AMP formation in an additive manner. 8-OH-PIPAT and 8-OH-DPAT, two selective 5-HT_1A agonists, produced a small but significant increase in cyclic AMP formation at concentrations above 0.04 μM and 10 μM, respectively. These findings suggest that at least three 5-HT receptor subtypes, i.e. 5-HT_1A, 5-HT₇ and 5-HT₄ receptors, are involved in mediating 5-HT-induced cyclic AMP formation in rat hippocampus.