Comparison of the effects of sertraline and its metabolite desmethylsertraline on blockade of central 5-HT reuptake in vivo.
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 s.c.) 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 micrograms/kg i.v.) nearly 20-fold the ED50 for sertraline (52 micrograms/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.
Sprouse
J
J
Department of Neuroscience, Pfizer Central Research, Groton, CT 06340, USA.
Clarke
T
T
Reynolds
L
L
Heym
J
J
Rollema
H
H
D015057:1-Naphthylamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D011903:Raphe Nuclei / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline / Q000031:analogs & derivatives; D013997:Time Factors
D015057:1-Naphthylamine; D011985:Receptors, Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; C065162:desmethylsertraline