| Autor: |
Nichols, Aaron L., Blumenfeld, Zack, Luebbert, Laura, Knox, Hailey J., Muthusamy, Anand K., Marvin, Jonathan S., Kim, Charlene H., Grant, Stephen N., Walton, David P., Cohen, Bruce N., Hammar, Rebekkah, Looger, Loren, Artursson, Per, Dougherty, Dennis A., Lester, Henry A. |
| Předmět: |
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| Zdroj: |
Journal of Neuroscience; 3/29/2023, Vol. 43 Issue 13, p2222-2241, 20p |
| Abstrakt: |
Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed treatment for individuals experiencing major depressive disorder. The therapeutic mechanisms that take place before, during, or after SSRIs bind the serotonin transporter (SERT) are poorly understood, partially because no studies exist on the cellular and subcellular pharmacokinetic properties of SSRIs in living cells. We studied escitalopram and fluoxetine using new intensity-based, drug-sensing fluorescent reporters targeted to the plasma membrane, cytoplasm, or endoplasmic reticulum (ER) of cultured neurons and mammalian cell lines. We also used chemical detection of drug within cells and phospholipid membranes. The drugs attain equilibrium in neuronal cytoplasm and ER at approximately the same concentration as the externally applied solution, with time constants of a few s (escitalopram) or 200--300 s (fluoxetine). Simultaneously, the drugs accumulate within lipid membranes by-18-fold (escitalopram) or 180-fold (fluoxetine), and possibly by much larger factors. Both drugs leave cytoplasm, lumen, and membranes just as quickly during washout. We synthesized membrane-impermeant quaternary amine derivatives of the two SSRIs. The quaternary derivatives are substantially excluded from membrane, cytoplasm, and ER for.2.4 h. They inhibit SERT transportassociated currents sixfold or 11-fold less potently than the SSRIs (escitalopram or fluoxetine derivative, respectively), providing useful probes for distinguishing compartmentalized SSRI effects. Although our measurements are orders of magnitude faster than the therapeutic lag of SSRIs, these data suggest that SSRI--SERT interactions within organelles or membranes may play roles during either the therapeutic effects or the antidepressant discontinuation syndrome. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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