Novel regulation of 5-HT1C receptors: down-regulation induced both by 5-HT1C/2 receptor agonists and antagonists

The 5-hydroxytryptamine1C (5-HT1C) receptor shares many features with the 5-HT2 receptor. To determine if the regulation of the sites is also similar we studied the effects of chronic treatment with drugs active at 5-HT1C/2 receptors on [3H]mesulergine-labelled 5-HT1C 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-HT1C sites with chronic injection compared to vehicle treatment. The 5-HT receptor antagonists 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 Kd 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 Bmax correlated significantly with its pKd (r = 0.84, P < 0.0007). This drug regulation pattern for 5-HT1C sites of down-regulation by both 5-HT1C/2 receptor agonists and antagonists is similar to that for 5-HT2 receptors and is consistent with the classification of 5-HT1C and 5-HT2 receptors in the same superfamily.