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-HT1A, h5-HT1B, and h5-HT1D receptors [guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding], and at h5-HT2A, h5-HT2B, and h5-HT2C receptors (depletion of membrane-bound [3H]phosphatydilinositol). All drugs stimulated h5-HT1A receptors with efficacies (compared with 5-HT, 100%) ranging from modest (apomorphine, 35%) to high (cabergoline, 93%). At h5-HT1B receptors, efficacies varied from mild (terguride, 37%) to marked (cabergoline, 102%) and potencies were modest (pEC50 values of 5.8–7.6): h5-HT1D sites were activated with a similar range of efficacies and greater potency (7.1–8.5). Piribedil and apomorphine were inactive at h5-HT1B and h5-HT1D receptors. At h5-HT2A 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-HT2B receptors. At 5-HT2C 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-HT2A and 5-HT2C 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-HT1A sites, their contrasting actions at 5-HT2A and 5-HT2C sites may be of particular significance to their functional profiles in vivo.
Footnotes
-
DOI: 10.1124/jpet.102.039883
- Abbreviations:
- 5-HT
- serotonin
- DA
- dopamine
- l-DOPA
- l-dihydroxyphenylacetic acid
- [35S]GTPγS
- guanosine 5′-O-(3-[35S]thio)triphosphate
- h
- human
- PI
- phosphatidylinositol
- CHO
- Chinese hamster ovary
- Received June 14, 2002.
- Accepted July 22, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
Log in using your username and password
Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$35.00
Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.