Further evidence that fluoxetine interacts with a 5-HT 2C receptor in glial cells

Abstract

It is generally believed that the antidepressant drug fluoxetine (Prozac) exerts all its effects by inhibition of serotonin uptake into neurons and an ensuing increase in the extracellular concentration of serotonin. However, these studies have confirmed and expanded our previous observation that fluoxetine on its own exerts agonist effects on astrocytes (a glial cell type), which resemble those exerted by serotonin. Fluoxetine appears to act on a different subtype of receptor (the 5-HT 2C receptor [in original terminology the 5-HT 1C receptor]) than the one on which micromolar concentrations of serotonin are known to act in astrocytes (the 5-HT 2A receptor [in original terminology the 5-HT 2 receptor]). However, this study has shown that application of serotonin to these cells stimulates glycogenolysis and causes an increase in free cytosolic concentration of calcium that is not inhibited by the 5-HT 2A selective antagonist, ketanserin. Moreover, both effects are pronounced at the low nanomolar level of serotonin and, therefore, by definition, act on the 5-HT 2C receptor. The concentration/response correlation is identical for the serotonin effects on free cytosolic calcium concentration and on glycogenolysis. Fluoxetine exerts similar effects, but low nanomolar concentrations have no effect, and the concentration required to obtain half-maximum response is 1–3 μM, a concentration dependence that is consistent with the plasma levels of fluoxetine during treatment with this drug. It is in accordance with the difference in subtype activation by fluoxetine and by micromolar concentrations of serotonin that chronic (1 wk) administration of 10 μM fluoxetine leads to a downregulation of the response to fluoxetine and to nanomolar concentration of serotonin but has little, if any, effect on the response to 1 μM serotonin. These results do not indicate that fluoxetine may not exert at least part of its therapeutic effects by inhibition of neuronal reuptake of serotonin, but they do show that concomitantly with this action fluoxetine exerts a direct effect on astrocytes that cannot be ignored when it is attempted to elucidate its mechanism of action.