Further Evidence That Fluoxetine Interacts with a 5-HT2C Receptor in Glial Cells

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-HT2C receptor [in original terminology the 5-HT1C receptor]) than the one on which micromolar concentrations of serotonin are known to act in astrocytes (the 5-HT2A receptor [in original terminology the 5-HT2 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-HT2A selective antagonist, ketanserin. Moreover, both effects are pronounced at the low nanomolar level of serotonin and, therefore, by definition, act on the 5-HT2C 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 microM, a concentration dependence that is consistent with the plasma levels of fluoxetine during treatment with this drug.(ABSTRACT TRUNCATED AT 250 WORDS)