Abstract
N-demethylation of the selective serotonin reuptake inhibitor sertraline to desmethylsertraline yields a compound with 10- to 20-fold less potency at blocking serotonin (5-HT) reuptake as measured in vitro. In the present study desmethylsertraline (DMS) was examined in two in vivo models of reuptake inhibition—elevation of extracellular 5-HT in the corpus striatum as measured by microdialysis and inhibition of firing of serotonin-containing dorsal raphe neurons. Whereas sertraline (1, 3.2, and 10 mg/kg SC) produced a dose-dependent increase in extracellular 5-HT and a decrease in 5-HIAA in rat striatum, desmethylsertraline was without effect on either parameter. In similar fashion, desmethylsertraline had no effect on dorsal raphe cell firing at a dose (1,000 μg/kg IV) nearly 20-fold the ED50 for sertraline (52 μg/kg). Taken together, these data suggest that DMS does not contribute to the blockade of central 5-HT reuptake produced by sertraline in vivo and therefore would be expected to play a negligible role in its clinical activity.
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Sprouse, J., Clarke, T., Reynolds, L. et al. Comparison of the Effects of Sertraline and Its Metabolite Desmethylsertraline on Blockade of Central 5-HT Reuptake In Vivo. Neuropsychopharmacol 14, 225–231 (1996). https://doi.org/10.1016/0893-133X(95)00112-Q
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DOI: https://doi.org/10.1016/0893-133X(95)00112-Q
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