COMPARISON OF DESMETHYLSERTRALINE WITH SERTRALINE AS A MONOAMINE UPTAKE INHIBITOR IN-VIVO

1. Desmethylsertraline, a metabolite of the antidepressant drug sertra line, was compared with sertraline for its ability to produce effects characteristic of inhibitors of the serotonin transporter in vivo. Des methylsertraline antagonized brain serotonin depletion by p-chloroamph etamine, a depletion dependent upon the serotonin transporter, being l ess potent than sertraline in rats but almost as potent as sertraline in mice. Desmethylsertraline was a weak antagonist of 6-hydroxydopamin e-induced depletion of heart norepinephrine in mice; sertraline had no effect at the doses studied. 2. Desmethylsertraline decreased brain c oncentrations of 5-hydroxyindoleacetic acid (5HIAA) in rats as did ser traline, the duration of the effect after both drugs being at least 24 hrs but less than 48 hrs. 3. After sertraline injection, desmethylser traline was present in rat brain at higher concentrations than the par ent drug at 8 hrs and thereafter. 4. In rats, repeated injections of s ertraline, at doses previously shown to diminish beta-adrenergic recep tor-mediated responses, led to marked accumulation of desmethylsertral ine in brain and to inhibition of the catecholamine transporters. 5. I n mice, brain concentrations of desmethylsertraline were higher than t hose of parent drug within 7 hrs after sertraline injection and probab ly contributed importantly to the antagonism of p-chloroamphetamine ef fects. 6. These data show that desmethylsertraline is less potent than sertraline as a serotonin uptake inhibitor in vivo, as the in vitro d ata would have predicted, but that desmethylsertraline may nonetheless contribute to the prolonged inhibition of the serotonin transporter a fter sertraline administration, perhaps more in mice than in rats.