Modulation of brainstem 5-HT 1C receptors by serotonergic drugs in the rat

Abstract

1. The sparse population of brainstem 5-hydroxytryptamine 1C (5-HT 1C) (also called 5-HT 2C) receptors has received little attention despite its possible role in the serotonin syndrome and 5-HT-mediated shaking behavior. We characterized [ 3H]mesulergine binding in rat brainstem and, to determine if brainstem 5-HT 1C sites respond to serotonergic manipulations, performed saturation studies of [ 3H]mesulergine binding in brainstem from rats treated chronically with 11 different 5-HT 1C/2 agonists and antagonists. 2. In competition studies in vitro, the rank order of drug potency was most compatible with a 5-HT 1C receptor binding site: mianserin, 5-HT, cinanserin, 1-(3-chlorophenyl)piperazine ( m-CPP), 1-(2-5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), MDL 100,907, RU 24969, 5-carboxamido-tryptamine (5-CT), 8-OH-DPAT, MDL 72,222. 3. Chronic treatment with the agonists quipazine and trifluoromethylphenylpiperazine (TFMPP) and the antagonists ritanserin and methiothepin significantly down-regulated brainstem 5-HT 1C sites, which were 65% of [ 3H]mesulergine-labeled sites in brainstem. Only metergoline and ritanserin significantly increased pK D. 4. Chronic treatment in vivo with DOI, m-CPP, mianserin, methysergide, spiperone, cyproheptadine, and metergoline had no significant effect on B MAX at the dose studied. 5. These data suggest similarities in the regulation of 5-HT 1C and 5-HT 2 sites at which both 5-HT 1C/2 agonists and antagonists also induce receptor down-regulation. 6. 5-HT 1C/2 agonists and antagonists that did not down-regulate brainstem 5-HT 1C sites may be more active in vivo at 5-HT 2 sites, at 5-HT 1C sites in other brain regions, have effects on 5-HT 1C receptors not detectable at the recognition site, or differ for pharmacokinetic reasons.