Differential Actions of Antiparkinson Agents at Multiple Classes of Monoaminergic Receptor. III. Agonist and Antagonist Properties at Serotonin, 5-HT1 and 5-HT2, Receptor Subtypes

• Published in: The Journal of pharmacology and experimental therapeutics 2002-11, Vol.303 (2), p.815
• Main Authors: Adrian Newman-Tancredi, Didier Cussac, Yann Quentric, Manuelle Touzard, Laurence Verrièle, Nathalie Carpentier, Mark J. Millan
• Format: Article
• Language: English
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.102.039883

Although certain antiparkinson agents interact with serotonin (5-HT) receptors, little information is available concerning functional actions. Herein, we characterized efficacies of apomorphine, bromocriptine, cabergoline, lisuride, piribedil, pergolide, roxindole, and terguride at human (h)5-HT 1A , h5-HT 1B , and h5-HT 1D receptors [guanosine 5′- O -(3-[ 35 S]thio)triphosphate ([ 35 S]GTPγS) binding], and at h5-HT 2A , h5-HT 2B , and h5-HT 2C receptors (depletion of membrane-bound [ 3 H]phosphatydilinositol). All drugs stimulated h5-HT 1A receptors with efficacies (compared with 5-HT, 100%) ranging from modest (apomorphine, 35%) to high (cabergoline, 93%). At h5-HT 1B receptors, efficacies varied from mild (terguride, 37%) to marked (cabergoline, 102%) and potencies were modest (pEC 50 values of 5.8–7.6): h5-HT 1D sites were activated with a similar range of efficacies and greater potency (7.1–8.5). Piribedil and apomorphine were inactive at h5-HT 1B and h5-HT 1D receptors. At h5-HT 2A receptors, terguride, lisuride, bromocriptine, cabergoline, and pergolide displayed potent (7.6–8.8) agonist properties (49–103%), whereas apomorphine and roxindole were antagonists and piribedil was inactive. Only pergolide (113%/8.2) and cabergoline (123%/8.6) displayed pronounced agonist properties at h5-HT 2B receptors. At 5-HT 2C receptors, lisuride, bromocriptine, pergolide, and cabergoline were efficacious (75–96%) agonists, apomorphine and terguride were antagonists, and piribedil was inactive. MDL100,907 and SB242,084, selective antagonists at 5-HT 2A and 5-HT 2C receptors, respectively, abolished these actions of pergolide, cabergoline, and bromocriptine. In conclusion, antiparkinson agents display markedly different patterns of agonist and antagonist properties at multiple 5-HT receptor subtypes. Although all show modest (agonist) activity at 5-HT 1A sites, their contrasting actions at 5-HT 2A and 5-HT 2C sites may be of particular significance to their functional profiles in vivo.