sertraline, Zoloft
Kinetics of the interaction of sertraline with the human platelet plasma membrane 5-hydroxytryptamine carrier.

Phillips OM, Wood KM, Williams DC.

Department of Biochemistry, Trinity College, Dublin, Ireland.

Sertraline, a new selective 5-HT uptake inhibitor showed a mixed pattern of inhibition of human platelet 5-HT uptake with a Ki value of 2.5 nM and K'i value of 25 nM. Imipramine and alaproclate were found to be fully competitive inhibitors of 5-HT uptake with Ki values of 8 and 130 nM respectively. Sertraline was a fully competitive inhibitor of high-affinity [3H]imipramine binding to platelet membranes with a Ki value of 1.3 nM, as was alaproclate and 5-HT with Ki values of 170 and 800 nM respectively. Both sertraline and imipramine, at a concentration of 10 microM caused a fast monophasic dissociation of [3H]imipramine from platelet membranes in contrast to serotonin which caused a slow monophasic dissociation.

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sertraline, Zoloft
Sertraline, 1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine, a new uptake inhibitor with selectivity for serotonin.

Koe BK, Weissman A, Welch WM, Browne RG.

Sertraline [1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine] was found to be a highly selective and potent competitive inhibitor of synaptosomal serotonin uptake. Sertraline also selectively reduced ex vivo uptake of serotonin and strongly antagonized the serotonin-depleting action of p-chloroamphetamine, indicating potent blockade of serotonin uptake in vivo. Acute and repeated dosing of sertraline decreased serotonin content of whole blood. Sertraline only weakly inhibited rat heart uptake of i.v. [3H]norepinephrine. In substantiation of selective blockade of serotonin uptake, sertraline potentiated various symptoms of 5-hydroxytryptophan but did not reverse reserpine-induced hypothermia. Sertraline was a very weak inhibitor of [3H]quinuclidinyl benzilate binding to rat brain membranes in vitro and did not produce anticholinergic effects 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-demethylsertraline, was also a selective serotonin uptake blocker. Sertraline strongly reduced immobility of mice in the Porsolt swim test for antidepressants. After repeated dosing in rats, sertraline diminished the cyclic AMP response of limbic forebrain adenylate cyclase to norepinephrine, as well as the binding of [3H]dihydroalprenolol to cortical membranes. It is proposed that selective blockade of serotonin reuptake can induce activation of norepinephrine neurons and subsequent down-regulation of norepinephrine receptors and that sertraline, a highly selective inhibitor of serotonin uptake, may be an efficacious antidepressant without anticholinergic or cardiovascular side-effects.

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sertraline, Zoloft
The effects of antidepressant treatment on serotonergic and dopaminergic systems in Fawn-Hooded rats: a quantitative autoradiography study.

Chen F, Lawrence AJ.

Department of Pharmacology, Faculty of Medicine, Monash University, Clayton, Victoria 3800, Australia. feng.chen med.monash.edu.au

Fawn-Hooded (FH) rats exhibit a phenotype including depressive behaviour and high alcohol preference, and as such tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) reduce alcohol consumption in this rat strain [Psychiatr. Genet. 12 (2002) 1-16]. However, the neurochemical effects of these antidepressants on monoamine systems in the brain, especially in mesolimbic areas have not been studied in FH rats. Therefore, the present study investigated neurochemical effects of subchronic treatment (10 days) with desipramine (DMI) and sertraline on several neurochemical markers of serotonin and dopamine systems. Binding to these markers including dopamine transporters (DATs), 5-HT transporters (SERTs), 5-HT(1A)- and 5-HT(2A)-receptors in rat brain sections was performed by quantitative autoradiography. The findings from the present study revealed that DMI and sertraline exhibited differential effects on SERTs and DATs in FH rat brain. For example, DMI caused a dramatic up-regulation of DATs whereas sertraline had no effect on DAT binding. In addition, both antidepressants showed some common and some differential effects on the binding to 5-HT(1A)- and 5-HT(2A)-receptors dependent upon region. These data demonstrate that DMI and sertraline differentially effect serotonergic and dopaminergic systems in mesolimbic regions in FH rats, suggesting that there may be different neurochemical mechanisms underlying their efficacy to reduce ethanol consumption in this animal model.

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sertraline, Zoloft
The effect of tianeptine and sertraline in three animal models of depression.

Kelly JP, Leonard BE.

Department of Pharmacology, University College, Galway, Ireland.

The activity of tianeptine (2.5 and 5.0 mg/kg twice daily, i.p.) and of sertraline (5.0 mg/kg, twice daily, i.p.) were assessed in three animal models of depression. In the Behavioural Despair Test, acute treatment with sertraline or tianeptine (5.0 mg/kg) significantly reduced the immobility time. In the olfactory bulbectomized (OB) rat model, chronic treatment with tianeptine (2.5 and 5.0 mg/kg) or sertraline (5.0 mg/kg) antagonized the lesion-induced hyperactivity in the "open field" apparatus. The hypothermic response to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.15 mg/kg, s.c.) was significantly attenuated after chronic setraline treatment, whereas tianeptine was inactive at the 2 doses tested. Neither drug affected the hypersection of corticosterone that occurs at the light:dark interface. A reduction in the serotonin metabolite 5-HIAA was found in the hypothalamus of sertraline-treated sham rats. It can be concluded that although the neurochemical properties of sertraline and tianeptine differ, they demonstrate similar antidepressant-like activities in the Behavioural Despair and OB rat models. The lack of effect of tianeptine on the 8-OH-DPAT-induced hypothermic effect indicates that it does not induce 5-HT1A subsensitivity, contrary to most antidepressants.

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sertraline, Zoloft
Comparison of desmethylsertraline with sertraline as a monoamine uptake inhibitor in vivo.

Fuller RW, Hemrick-Luecke SK, Littlefield ES, Audia JE.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.

1. Desmethylsertraline, a metabolite of the antidepressant drug sertraline, was compared with sertraline for its ability to produce effects characteristic of inhibitors of the serotonin transporter in vivo. Desmethylsertraline antagonized brain serotonin depletion by p-chloroamphetamine, a depletion dependent upon the serotonin transporter, being less potent than sertraline in rats but almost as potent as sertraline in mice. Desmethylsertraline was a weak antagonist of 6-hydroxydopamine-induced depletion of heart norepinephrine in mice; sertraline had no effect at the doses studied. 2. Desmethylsertraline decreased brain concentrations of 5-hydroxyindoleacetic acid (5HIAA) in rats as did sertraline, the duration of the effect after both drugs being at least 24 hrs but less than 48 hrs. 3. After sertraline injection, desmethylsertraline was present in rat brain at higher concentrations than the parent drug at 8 hrs and thereafter. 4. In rats, repeated injections of sertraline, at doses previously shown to diminish beta-adrenergic receptor-mediated responses, led to marked accumulation of desmethylsertraline in brain and to inhibition of the catecholamine transporters. 5. In mice, brain concentrations of desmethylsertraline were higher than those of parent drug within 7 hrs after sertraline injection and probably contributed importantly to the antagonism of p-chloroamphetamine effects. 6. These data show that desmethylsertraline is less potent than sertraline as a serotonin uptake inhibitor in vivo, as the in vitro data would have predicted, but that desmethylsertraline may nonetheless contribute to the prolonged inhibition of the serotonin transporter after sertraline administration, perhaps more in mice than in rats.

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sertraline, Zoloft
Further evidence of anticonvulsant role for 5-hydroxytryptamine in genetically epilepsy-prone rats.

Yan QS, Jobe PC, Dailey JW.

Department of Basic Sciences, University of Illinois College of Medicine at Peoria 61656, USA.

1. This study was designed to evaluate further the role of 5-hydroxytryptamine (5-HT) in regulating susceptibility and/or intensity of audiogenic seizures in genetically epilepsy-prone rats. 2. The effects of sertraline, a highly selective and potent inhibitor of 5-HT uptake, on both the intensity of the audiogenic seizures and the extracellular concentrations of 5-HT in the thalamus were evaluated in severe seizure genetically epilepsy-prone rats. 3. Sertraline (7.5, 15 and 30 mg kg-1, i.p.) produced a dose-dependent reduction in the intensity of the audiogenic seizures. 4. Brain microdialysis studies showed that the same doses of sertraline also caused dose-dependent increases in the extracellular 5-HT concentration in the thalamus of the freely moving rats. 5. The peak anticonvulsant effect correlated temporally with the peak increases in the extracellular 5-HT concentration for this drug. 6. It is concluded that enhancement of 5-hydroxytryptaminergic transmission may contribute to the anticonvulsant effect of sertraline in severe seizure genetically epilepsy-prone rats. 7. The present results coupled with earlier investigations support the hypothesis that 5-HT plays an anticonvulsant role in genetically epilepsy-prone rats.

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sertraline, Zoloft
Postmarketing surveillance by patient self-monitoring: preliminary data for sertraline versus fluoxetine.

Fisher S, Kent TA, Bryant SG.

Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston 77555, USA.

BACKGROUND: There have been no published postmarketing reports comparing sertraline with another serotonin selective reuptake inhibitor (SSRI) in large-sample, parallel groups. As part of an ongoing postmarketing surveillance study, this paper presents preliminary data for a number of adverse clinical events reported by outpatients being treated with either fluoxetine or sertraline. METHOD: Using a well-validated method developed to signal possible adverse drug reactions, data were collected on 1577 fluoxetine-treated and 1209 sertraline-treated patients who filled a prescription for either of the two targeted drugs. Pharmacists gave these patients an announcement, part of which served as an entry form, that described the purpose and details of the study. Volunteers (highly selective) were requested to report during the next month via a toll-free telephone interview "any new or unusual symptoms or unexpected improvements" in their health since starting the designated medication. RESULTS: Almost 1 (31.4%) of every 3 sertraline-treated patients called at least once to report one or more adverse clinical events compared with only about 1 (19.7%) of every 5 fluoxetine-treated patients. Most of the reported adverse clinical events--but not all--are well-known adverse drug reactions that seem common to SSRIs. Adverse clinical events reported more frequently by sertraline-treated patients included urinary, sexual, psychological, neurologic, gastrointestinal, and dermatological complaints. Drug discontinuation was also reported more frequently by sertraline-treated patients. Fluoxetine-treated patients reported an increased frequency of weight gain and anger or aggression. CONCLUSION: These data indicate that many adverse reactions known to be induced by fluoxetine are being reported with even greater frequency by sertraline-treated patients. Possible interpretations of these differences are discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7615482&dopt=Abstract sertraline Zoloft