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 selective 5-HT uptake inhibitor, fluoxetine (10 mg/kg, i.p.) increased extracellular 5-HT levels in rat hypothalamus up to 260 percent of basal levels. (-)-Pindolol, and antagonist at the somatodendritic 5-HT1A autoreceptor, dose-dependently (1, 3 and 5 mg/kg, s.c.) potentiated the fluoxetine dependent increase up to 458 percent of basal 5-HT levels for approximately 1.5 hours. Continuous infusion of ( +/- )-pindolol at 30 mg/kg/h s.c. enhanced the fluoxetine dependent elevation of extracellular 5-HT concentrations in hypothalamus up to 464 percent of basal levels and lasted for 3 hours. Thus, the combination of 5-HT uptake inhibition with antagonism at the somatodendritic 5-HT1A autoreceptor can enhance 5-HT release to levels beyond those achieved with uptake inhibition alone. The present findings are consistent with the hypothesis that blockade of somatodendritic 5-HT1A autoreceptors removes the inhibitory effect exerted by the elevated 5-HT levels resulting from uptake inhibition.
Dreshfield
L J
LJ
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Wong
D T
DT
Perry
K W
KW
Engleman
E A
EA
D000704:Analysis of Variance; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007263:Infusions, Parenteral; D007700:Kinetics; D008297:Male; D017551:Microdialysis; D010869:Pindolol / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*
D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D005473:Fluoxetine; D012701:Serotonin; D010869:Pindolol