ENHANCEMENT OF FLUOXETINE-DEPENDENT INCREASE OF EXTRACELLULAR SEROTONIN (5-HT) LEVELS BY (-)-PINDOLOL, AN ANTAGONIST AT 5-HT1A RECEPTORS

The somatodendritic 5-HT1A autoreceptor is known to regulate activity of 5-HT neurons and consequently 5-HT release. Administration of a sel ective 5-HT uptake inhibitor, fluoxetine (10 mg/kg, i.p.) increased ex tracellular 5-HT levels in rat hypothalamus up to 260 percent of basal levels. (-)-Pindolol, an antagonist at the somatodendritic 5-HT1A aut oreceptor, dose-dependently (1, 3 and 5 mg/kg, s.c.) potentiated the f luoxetine dependent increase up to 458 percent of basal 5-HT levels fo r approximately 1.5 hours. Continuous infusion of (+/-)-pindolol at 30 mg/kg/h s.c. enhanced the fluoxetine dependent elevation of extracell ular 5-HT concentrations in hypothalamus up to 464 percent of basal le vels and lasted for 3 hours. Thus, the combination of 5-HT uptake inhi bition with antagonism at the somatodendritic 5-HT1A autoreceptor can enhance 5-HT release to levels beyond those achieved with uptake inhib ition alone. The present findings are consistent with the hypothesis t hat blockade of somatodendritic 5-HT1A autoreceptors removes the inhib itory effect exerted by the elevated 5-HT levels resulting from uptake inhibition.