The GABA(A) receptor complex as a target for fluoxetine action.
The clinically important antidepressant fluoxetine is established as a selective serotonin reuptake inhibitor. This study demonstrates that fluoxetine also interacts with the GABA(A) receptor complex. At concentrations above 10 microM fluoxetine inhibited the binding of both [3H]GABA (IC50 = 2 mM) and [3H]flunitrazepam (IC50 = 132 microM) to the GABA(A) receptor complex in brain cortical membranes. Low fluoxetine concentrations (1 nM) enhanced GABA-stimulated Cl- uptake by a rat cerebral cortical vesicular preparation. At higher concentrations (100 microM and 1 mM), however, fluoxetine inhibited GABA-stimulated Cl- uptake, an effect related to a reduction in Emax. These observations might assist in an explanation of the basis of the antidepressant action of fluoxetine.
Tunnicliff
G
G
Department of Biochemistry, Indiana University School of Medicine, Evansville 47712, USA. gtunnic@iupui.edu
Schindler
N L
NL
Crites
G J
GJ
Goldenberg
R
R
Yochum
A
A
Malatynska
E
E
D000818:Animals; D002712:Chlorides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005445:Flunitrazepam / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology*; D017136:Ion Transport; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D002712:Chlorides; D005445:Flunitrazepam; D005473:Fluoxetine; D011963:Receptors, GABA-A; D017367:Selective Serotonin Reuptake Inhibitors; D014316:Tritium; D005680:gamma-Aminobutyric Acid