Abstract

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-[³⁵S]thio)triphosphate ([³⁵S]GTPγS) binding], and at h5-HT_2A, h5-HT_2B, and h5-HT_2C receptors (depletion of membrane-bound [³H]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 (pEC₅₀ 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.