EFFECTS OF 5-HT1A RECEPTOR ANTAGONISTS ON FLUOXETINE-INDUCED CHANGES IN EXTRACELLULAR SEROTONIN CONCENTRATIONS IN RAT FRONTAL-CORTEX

Clinical studies in which serotonin specific reuptake inhibitors have been co-administered with pindolol have demonstrated a shortened time to onset of antidepressant activity. This effect has been attributed t o the antagonist effects of pindolol at the presynaptic 5-HT1A recepto r which augments the action of the serotonin specific reuptake inhibit ors. In the present study, we demonstrate that acute fluoxetine-induce d increases in extracellular serotonin concentrations, as measured by microdialysis in the frontal cortex, can be potentiated by 5-HT1A rece ptor blockade using razinyl]ethyl]-N-(pyridinyl)cyclohexanecarboxamide (WAY100635), the silent and selective 5-HT1A receptor antagonist. WAY 100635 at doses as low as 0.03 mg/kg s.c. maintained this potentiation effect across a range of fluoxetine doses. In addition, using antagon ists with different intrinsic agonist activities for the 5-HT1A recept or, we have determined that only compounds with very low intrinsic ago nist activity can produce a potentiation of the acute fluoxetine-induc ed increases in extracellular serotonin. (C) 1998 Elsevier Science B.V .