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.
Szasz
Bernadett K
BK
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony u.43, Budapest, Hungary.
Mike
Arpad
A
Karoly
Robert
R
Gerevich
Zoltan
Z
Illes
Peter
P
Vizi
E Sylvester
ES
Kiss
Janos P
JP
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