Enhancement in extracelllar serotonin levels by 5-hydroxytryptophan loading after administration of WAY 100635 and fluoxetine

It has been demonstrated that synthesis of serotonin (5-HT) is dependent on the availability of precursor, as well as the activity of 5-HT neurons. In the present series of experiments, we examined the effects of precursor (5 -HTP) loading on extracellular hypothalamic 5-HT after administration of fl uoxetine alone or in combination with WAY 100635, a selective 5-HT1A antago nist. In the first experiment, fluoxetine alone (10 mg/kg i.p.) caused 5-HT levels to significantly increase to 150% of basal levels. Subsequent admin istration of 5-HTP at 10, 20, and 40 mg/kg i.p. caused 5-HT levels to furth er increase to a maximum value of 254%, 405%, and 618%, respectively. In th e second experiment, either vehicle or WAY 100635 (1 mg/kg/hour s.c.) was i nfused, then fluoxetine (10 mg/kg i.p.) and 5-HTP (10 mg/kg i.p.) were admi nistered. By itself, WAY 100635 led to a slight but significant increase in hypothalamic 5-HT levels one hour after the start of administration (130% of basal levels). In the WAY 100635-treated group, fluoxetine caused an inc rease to 240% of basal levels after one hour, which rose to 290% of basal l evels after two hours. Subsequent administration of 5-HTP further increased 5-HT levels to 580% of basal levels after one hour. In the vehicle-treated group, fluoxetine caused an increase of 160% of basal levels which was sta ble over two hours, and subsequent administration of 5-HTP led to a slight increase in 5-HT levels of 220% after one hour. These results suggest that combining blockade of 5-HT1A autoreceptors with 5-HT uptake inhibition resu lts in a synergistic increase in synthesis and release of 5-HT when precurs or is administered.