Novel regulation of 5-HT 1C receptors: down-regulation induced both by 5-HT 1C/2 receptor agonists and antagonists

Abstract

The 5-hydroxytryptamine 1C (5-HT 1C) receptor shares many features with the 5-HT 2 receptor. To determine if the regulation of the sites is also similar we studied the effects of chronic treatment with drugs active at 5-HT 1C/2 receptors on [ 3H]mesulergine-labelled 5-HT 1C binding sites in spinal cord. The 5-HT receptor agonists 1-(3-chlorophenyl)piperazine (m-CPP) (-38%), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (-35%), quipazine (-27%) and m-trifluoromethylphenylpiperazine (TFMPP) (-27%) significantly down-regulated spinal 5-HT 1C sites with chronic injection compared to vehicle treatment. The 5-HT receptor antagonist methiothepin (-71%), mianserin (-24%), methysergide (-21%), and cyproheptadine (-27%) also induced down-regulation, and ritanserin and metergoline further reduced [ 3H]mesulergine specific binding to undetectable levels. There were no significant changes in K d to implicate presence of residual drug except for mianserin, methiothepin, and TFMPP. Pindolol and spiperone had no significant effects. In acute dose-response studies, injection of a single dose of DOI did not result in a significant change in any receptor parameters. The capacity of a drug to lower B max correlated significantly with its pK d ( r = 0.84, P < 0.0007). This drug regulation pattern for 5-HT 1C sites of down-regulation by both 5-HT 1C/2 receptor agonists and antagonists is similar to that for 5-HT 2 receptors and is consistent with the classification of 5-HT 1C and 5-HT 2 receptors in the same superfamily.