Pharmacological characterisation of 5-HT receptors positively coupled to adenylyl cyclase in the rat hippocampus.
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.
Markstein
R
R
Nervous System Research, Novartis Pharma AG, Basel, Switzerland. rudolf.markstein@pharma.novartis.com
Matsumoto
M
M
Kohler
C
C
Togashi
H
H
Yoshioka
M
M
Hoyer
D
D
D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology*; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C104425:serotonin 7 receptor; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases