Enhancement of the anticonvulsant effect of fluoxetine following blockade of 5-HT1A receptors.
Serotonin reuptake inhibitors, such as fluoxetine, have been shown to exert anticonvulsant effects in several animal models of epilepsy. In view of recent studies showing that 5-HT1A receptor antagonists (somatodendritic autoreceptor antagonists) enhance the increase in extracellular 5-hydroxytryptamine (5-HT, serotonin) produced by serotonin reuptake inhibitors, it was of interest to determine if these antagonists also enhance the anticonvulsant effect of fluoxetine in Genetically Epilepsy-Prone Rats (GEPRs). The 5-HT1A receptor antagonists (-)-pindolol and LY 206130 (1-[1-H-indol-4-yloxy]-3-[cyclohexylamino]-2-propanol maleate) were examined in the present study and both enhanced the anticonvulsant action of fluoxetine in severe seizure GEPRs (GEPR-9s). The latter effect of LY 206130 was found to be dose- and 5-HT-dependent. These findings provide further evidence that the increase in extracellular serotonin observed after administering fluoxetine in combination with a 5-HT1A receptor antagonist is physiologically important and that the anticonvulsant effect of fluoxetine in the GEPR is mediated through an increase in extracellular 5-HT.
Browning
R A
RA
Department of Physiology, Southern Illinois University School of Medicine, Carbondale, USA.
Wood
A V
AV
Merrill
M A
MA
Dailey
J W
JW
Jobe
P C
PC
D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003514:Cyclohexylamines / Q000627:therapeutic use; D004347:Drug Interactions; D005260:Female; D010134:Fenclonine / Q000494:pharmacology; D005473:Fluoxetine / Q000627:therapeutic use*; D009638:Norepinephrine / Q000378:metabolism; D010869:Pindolol / Q000627:therapeutic use; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012640:Seizures / Q000188:drug therapy*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000627:therapeutic use*
D000927:Anticonvulsants; D003514:Cyclohexylamines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D005473:Fluoxetine; C098407:LY 206130; D012701:Serotonin; D010869:Pindolol; D010134:Fenclonine; D009638:Norepinephrine