Antagonism of serotonin 5-HT1A receptors potentiates the increases in extracellular monoamines induced by duloxetine in rat hypothalamus.
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.
Engleman
E A
EA
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Robertson
D W
DW
Thompson
D C
DC
Perry
K W
KW
Wong
D T
DT
D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D003514:Cyclohexylamines / Q000494:pharmacology; D004357:Drug Synergism; D000068736:Duloxetine Hydrochloride; D005110:Extracellular Space / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*
D015306:Biogenic Monoamines; D003514:Cyclohexylamines; D000068736:Duloxetine Hydrochloride; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes; C098407:LY 206130