Abstract
The present study investigated the functional antagonism of different antidepressants on 5-HT3 receptor function and the role of lipid rafts for these modulatory effects. Electrophysiological recordings of 5-HT evoked cation currents were recorded with N1E-115 and HEK-5-HT3A cells and hippocampal neurons. The characterization of the antagonism of antidepressants was made by the displacement of [3H]GR65630 binding. For membrane fractionation, sucrose density gradient centrifugation was used. Gradient fractions were assayed for antidepressant concentrations by HPLC; 5-HT3 receptor membrane distribution was determined by Western blot. Colocalization experiments were performed by means of immunocytochemistry. Most antidepressants acted as non-competitive antagonists at the 5-HT3 receptor. Moreover, some of these compounds were enriched within lipid rafts. Cholesterol depletion impaired lipid raft integrity thereby affecting 5-HT3 receptor function, whereas the antagonistic effects of antidepressants were not altered.In conclusion, most antidepressants directly antagonize 5-HT3 receptor activity. 5-HT3 receptor function per se appears to depend on lipid raft integrity, which is, however, not a prerequisite for the modulatory potency of antidepressants at this receptor.
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Correspondence
C. NothdurfterMD
Department of Psychiatry and
Psychotherapy
Ludwig-Maximilians-University
Munich
Nußbaumstraße 7
80336 Munich
Germany
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Fax: +49/89/5160 5391
eMail: Caroline.Nothdurfter@med.uni-muenchen.de