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 sertrali ne to desmethylsertraline yields a compound with 10- to 20-fold less p otency at blocking serotonin (5-HT) reuptake as measured in vitro. In the present study desmethylsertraline (DMS) was examined in two in viv o models of reuptake inhibition-elevation of extracellular 5-HT in the corpus striatum as measured by microdilaysis 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 extracellul ar 5-HT and a decrease in 5-HIAA in rat striatum, desmethylsertraline was without effect on either parameter. In similar fashion, desmethyls ertraline had no effect on dorsal raphe cell firing at a dose (1,000 m u g/kg IV) nearly 20-fold the ED(50) for sertraline (52 mu g/kg). Take n together, these data suggest that DMS does not contribute to the blo ckade of central 5-HT reuptake produced by sertraline in vivo and ther efore would be expected to play a negligible role in its clinical acti vity.