Effects of 5-HT1A receptor antagonists on fluoxetine-induced changes in extracellular serotonin concentrations in rat frontal cortex.
Clinical studies in which serotonin specific reuptake inhibitors have been co-administered with pindolol have demonstrated a shortened time to onset of antidepressant activity. This effect has been attributed to the antagonist effects of pindolol at the presynaptic 5-HT1A receptor which augments the action of the serotonin specific reuptake inhibitors. In the present study, we demonstrate that acute fluoxetine-induced increases in extracellular serotonin concentrations, as measured by microdialysis in the frontal cortex, can be potentiated by 5-HT1A receptor blockade using N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexa necarboxamide (WAY100635), the silent and selective 5-HT1A receptor antagonist. WAY100635 at doses as low as 0.03 mg/kg s.c. maintained this potentiation effect across a range of fluoxetine doses. In addition, using antagonists with different intrinsic agonist activities for the 5-HT1A receptor, we have determined that only compounds with very low intrinsic agonist activity can produce a potentiation of the acute fluoxetine-induced increases in extracellular serotonin.
Dawson
L A
LA
CNS Disorders Division, Wyeth-Ayerst Research, Princeton, NJ 08543-8000, USA. dawsonl@war.wyeth.com
Nguyen
H Q
HQ
D000818:Animals; D002065:Buspirone / Q000494:pharmacology; D003510:Cyclohexanes / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D002065:Buspirone; D003510:Cyclohexanes; D005473:Fluoxetine; D010879:Piperazines; D011725:Pyridines; D012701:Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C112802:WAY 101363; C081293:WAY 100135; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide