Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT(2C) receptor

Abstract

Interactions of the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine and its main metabolite norfluoxetine, and the tricyclic antidepressant (TCA) imipramine with the rat serotonin 5-HT(2C) receptor in a clonal cell line and in the rat choroid plexus were investigated by radioligand binding and phosphoinositide (PI) hydrolysis assays. For comparison, the affinities of a variety of other antidepressants of different chemical classes for the cloned rat 5-HT(2C) and 5-HT(2A) receptors were also determined by radioligand binding assays. Fluoxetine displayed relatively high affinity for the 5-HT(2C) receptor in the choroid plexus, with a K(i) value for inhibition of [3H]mesulergine binding of 55.4 nM. The K(i) values for imipramine, norfluoxetine and citalopram were 136 nM, 203 nM, and 298 nM, respectively. Similar rank order of potency was detected in PI hydrolysis assays, which showed that these drugs are antagonists at the 5-HT(2C) receptor without exhibiting inverse agonist activity. [3H]Ketanserin (5-HT(2A)) binding assays revealed that the SSRIs fluoxetine, norfluoxetine and citalopram show 10- to 23-fold selectivity for the 5-HT(2C) receptor in vitro, whereas the TCA imipramine does not. Many other TCAs also had high to intermediate affinity for both 5-HT(2A) and 5-HT(2C) receptors. The present data provide evidence that fluoxetine, norfluoxetine and citalopram, along with many other antidepressant compounds, interact directly with the 5-HT(2C) receptor.