Dennis Charles Thompson

Antagonism of Serotonin 5‐HT1A Receptors Potentiates the Increases in Extracellular Monoamines Induced by Duloxetine in Rat Hypothalamus

Abstract: In the current study we examined the effects of coadministration of a serotonin 5‐HT1A antagonist, (±)‐1‐(1H‐indol‐4‐yloxy)‐3‐(cyclohexylamino)‐2‐propanol maleate (LY 206130), and a dual 5‐HT and norepinephrine (NE) uptake inhibitor, duloxetine, on extracellular levels of NE, 5‐HT, dopamine (DA), 5‐hydroxyindoleacetic acid, and 3,4‐dihydroxyphenylacetic acid in rat hypothalamus microdialysates. LY 206130 (3.0 mg/kg, s.c.) alone significantly increased NE and DA levels by 60 and 34%, respectively, without affecting 5‐HT levels. Duloxetine administration at 4.0 mg/kg, i.p. alone produced no significant changes in levels of 5‐HT, NE, or DA. In contrast, when LY 206130 and duloxetine were coadministered at 3.0 mg/kg, s.c. and 4.0 mg/kg, i.p., respectively, 5‐HT, NE, and DA levels increased to 5.7‐, 4.8‐, and threefold over their respective basal levels. These data demonstrate that antagonism of somatodendritic 5‐HT1A autoreceptors and concomitant inhibition of 5‐HT and NE uptake with duloxetine may promote synergistic increases in levels of extracellular 5‐HT, NE, and DA in hypothalamus of conscious, freely moving rats.

Enhancement in extracellular 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 fluoxetine alone or in combination with WAY 100635, a selective 5-HT1A antagonist. In the first experiment, fluoxetine alone (10 mg/kg i.p.) caused 5-HT levels to significantly increase to 150% of basal levels. Subsequent administration of 5-HTP at 10, 20, and 40 mg/kg i.p. caused 5-HT levels to further increase to a maximum value of 254%, 405%, and 618%, respectively. In the second experiment, either vehicle or WAY 100635 (1 mg/kg/hour s.c.) was infused, then fluoxetine (10 mg/kg i.p.) and 5-HTP (10 mg/kg i.p.) were administered. 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 increase to 240% of basal levels after one hour, which rose to 290% of basal levels 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 stable 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 results in a synergistic increase in synthesis and release of 5-HT when precursor is administered.