FURTHER EVIDENCE THAT FLUOXETINE INTERACTS WITH A 5-HT2C RECEPTOR IN GLIAL-CELLS

It is generally believed that the antidepressant drug fluoxetine (Proz ac) exerts all its effects by inhibition of serotonin uptake into neur ons and an ensuing increase in the extracellular concentration of sero tonin, However, these studies have confirmed and expanded our previous observation that fluoxetine on its own exerts agonist effects on astr ocytes (a glial cell type), which resemble those exerted by serotonin, Fluoxetine appears to act on a different subtype of receptor (the 5-H T2C receptor [in original terminology the 5-HT1C receptor]) than the o ne on which micromolar concentrations of serotonin are known to act in astrocytes (the 5-HT2A receptor [in original terminology the 5-HT2 re ceptor]). However, this study has shown that application of serotonin to these cells stimulates glycogenolysis and causes an increase in fre e cytosolic concentration of calcium that is not inhibited by the 5-HT 2A selective antagonist, ketanserin, Moreover, both effects are pronou nced at the low nanomolar level of serotonin and, therefore, by defini tion, act on the 5-HT2C receptor. The concentration/response correlati on is identical for the serotonin effects on free cytosolic calcium co ncentration 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 mu M, a concentration dependence that is consistent with the plasma levels of fluoxetine du ring 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 mu M fluoxetine leads to a downregulation of the response to fluoxetine and to nanomol ar concentration of serotonin but has little, if any, effect on the re sponse to 1 mu M serotonin, These results do not indicate that fluoxet ine may not exert at least part of its therapeutic effects by inhibiti on of neuronal reuptake of serotonin, but they do show that concomitan tly with this action fluoxetine exerts a direct effect on astrocytes t hat cannot be ignored when it is attempted to elucidate its mechanism of action.