Differential effects of coadministration of fluoxetine and WAY-100635 on serotonergic neurotransmission in vivo: Sensitivity to sequence of injections

Serotonin 5-HT1A receptor antagonists potentiate the effects of serotonin r euptake inhibitors on extracellular serotonin levels in a variety of brain regions. These effects are quite variable, however, with reports indicating potentiations of anywhere from 100-1900%. One factor that might impact the magnitude of such potentiations is the timing of administration of the two agents; reports in which the reuptake inhibitor is given prior to the sero tonin receptor antagonist consistently report larger potentiations than rep orts in which the antagonist is given first. To test this relationship dire ctly, microdialysis and electrophysiology studies were performed to assess the magnitude of increase in extracellular serotonin and changes in cellula r activity produced by the serotonin reuptake inhibitor fluoxetine and the 5-HT1A receptor antagonist WAY-100635 under various dosing regimens. In mic rodialysis studies, when WAY-100635 (0.5 mg/kg s.c.) was administered 80 mi n after fluoxetine (10 mg/kg i.p.) the increase in serotonin was more than twice that observed when the compounds were coadministered. In electrophysi ology studies in vivo, WAY-100635 reversed the depression of cell firing pr oduced by fluoxetine when administered 30 min after fluoxetine, but when th e two compounds were coadministered, a depression in firing rate was observ ed comparable to that produced by fluoxetine alone. In contrast, slice reco rding studies showed that WAY-100635 blocked the effects of fluoxetine rega rdless of the order of administration. These results indicate that fluoxeti ne and WAY-100635 can interact in a fashion not predicted by the currently accepted model. It is likely that neuronal circuitry outside of the raphe n uclei underlies this relationship. Synapse 38:17-26, 2000. (C) 2000 Wiley-L iss, Inc.