SERTRALINE, 1S,4S-N-METHYL-4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDRO-1-NAPHTHYLAMINE, A NEW UPTAKE INHIBITOR WITH SELECTIVITY FOR SEROTONIN

  • 1 January 1983
    • journal article
    • research article
    • Vol. 226  (3) , 686-700
Abstract
Sertraline[1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthylamine] was a highly selective and potent competitive inhibitor of synaptososmal serotonin [5-HT] uptake. Sertraline also selectively reduced ex vivo uptake of 5-HT and strongly antagonized the 5-HT depleting action of p-chloroamphetamine,indicating potent blockade of 5-HT uptake in vivo. Acute and repeated dosing of sertraline decreaed 5-HT content of whole blood. Sertraline only weakly inhibited rat heart uptake of i.v. [3H]norepinephrine. In substantiation of selective blockade of 5-HT uptake, sertraline potentiated various symptoms of 5-hydroxytryptophan but did not reverse reserpine-induced hypothermia. Sertraline was a weak inhibitor of [3H]quinuclidinyl benzilate binding to rat brain membranes in vitro and did not produce anticholinergic effect in mice in vivo. Sertraline was well tolerated in mice, rats and dogs, with no locomotor stimulant effects in rats or untoward cardiovascular effects in dogs. The major metabolite, N-demethylsertraine, was also a selective 5-HT uptake blocker. Sertraline strongly reduced immobility of mice in the Porsolt swim test for antidepressants. After repeated dosing in rats, sertraline diminished the cAMP response of limbic forebrain adenylate cyclase to norepinephrine, as well as the binding of [3H]dihydroalprenolol to cortical membranes. Evidently, selective blockade of 5-HT reuptake can induce activation of norepinepherine neurons and subsequent down-regulation of norepinephrine receptors and sertraline, a highly selective inhibitor of 5-HT uptake, may be an efficacious antidepressant without anticholinergic or cardiovascular side-effects.