Direct inhibitory effect of fluoxetine on N-methyl-D-aspartate receptors in the central nervous system.
BACKGROUND
Data accumulated in the last decade indicate that N-methyl-D-aspartate (NMDA) receptors might be involved in the pathophysiology of depression and the mechanism of action of antidepressants, although a direct inhibitory effect has been reported only in connection with tricyclic compounds, which interact with a wide range of receptors.


METHODS
Using whole-cell patch-clamp recording in rat cortical cell cultures, we investigated whether the selective serotonin reuptake inhibitor fluoxetine, which has a much better adverse effect profile, has a direct effect on NMDA receptors, and we compared its action to that of the tricyclic desipramine.


RESULTS
Both desipramine (concentration that causes 50% inhibition (IC(50)) = 3.13 microM) and fluoxetine (IC(50) = 10.51 microM) inhibited NMDA-evoked currents with similar efficacy in the clinically relevant low micromolar concentration range. However, in contrast to desipramine, the inhibition by fluoxetine was not voltage-dependent, and fluoxetine partially preserved its ability to associate with NMDA receptor in the presence of Mg(2+), suggesting different binding sites for the two drugs.


CONCLUSIONS
The fact that different classes of antidepressants were found to be low-affinity NMDA antagonists suggests that direct inhibition of NMDA receptors may contribute to the clinical effects of antidepressants.
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony u.43, Budapest, Hungary.
Bernadett K
BK
Szasz
Arpad
A
Mike
Robert
R
Karoly
Zoltan
Z
Gerevich
Peter
P
Illes
E Sylvester
ES
Vizi
Janos P
JP
Kiss
D000465:Algorithms; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001665:Binding Sites; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects*; D002540:Cerebral Cortex / Q000166:cytology; D003891:Desipramine / Q000494:pharmacology; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D008274:Magnesium / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D005473:Fluoxetine; D008274:Magnesium; D003891:Desipramine