sertraline, Zoloft
Metabolism and disposition of the 5-hydroxytryptamine uptake blocker sertraline in the rat and dog.

Tremaine LM, Welch WM, Ronfeld RA.

Drug Metabolism Department, Central Research, Pfizer, Inc., Groton, CT 06340.

Sertaline [1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- naphthalenamine] is a potent and selective inhibitor of neuronal serotonin uptake and is currently under development for the treatment of depression and of obesity. The drug is greater than 97% bound to plasma proteins, yet extensively distributes into tissues. The whole brain concentration of sertraline in the rat is more than 40-fold higher than that in plasma, and the volume of distribution is about 25 liters/kg in the rat and dog. Sertraline is extensively metabolized by the rat and dog prior to excretion. The metabolic clearance of sertraline is greater than 35 ml of blood/min/kg in each species, and first-pass metabolism occurs with oral administration. Initial metabolic steps include N-demethylation, N-hydroxylation, oxidative deamination, and glucuronidation of sertraline carbamic acid, which in solution is in equilibrium with sertraline and carbon dioxide. The N-desmethyl metabolite, which is 10-fold less potent as an inhibitor of serotonin uptake, is formed in both species. Plasma AUC for desmethyl-sertraline is 66 to 270% of that for sertraline, and is dependent on the species examined and route of drug administration. Sertraline and desmethyl-sertraline undergo oxidative deamination to the corresponding ketone, which is subsequently hydroxylated at the alpha-carbon, forming a diastereomeric metabolite pair. The glucuronides of sertraline carbamic acid, N-hydroxy sertraline, and the alpha-hydroxy ketone diastereomers comprise 45% and 82% of the total radiolabel excreted in urine and bile of bile duct-cannulated rats and dogs, respectively. Bile is the major route of elimination in both species.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2573498&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Sertraline, a selective inhibitor of serotonin uptake, induces subsensitivity of beta-adrenoceptor system of rat brain.

Koe BK, Koch SW, Lebel LA, Minor KW, Page MG.

Department of Pharmacology, Pfizer Inc., Groton, CT 06340.

Subacute administration (b.i.d. for 4 days) of sertraline, a potent and selective inhibitor of serotonin uptake, was found to reduce cyclic AMP generation by the norepinephrine receptor-coupled adenylate cyclase in rat limbic forebrain slices and decrease the number of beta-adrenoceptors in rat cerebral cortex without affecting the affinity of [3H]dihydroalprenolol binding. Co-administration of sertraline and the serotonin agonist, quipazine, at doses at which neither agent had an effect, resulted in desensitization of norepinephrine receptor-coupled adenylate cyclase and down-regulation of beta-adrenoceptors. These findings suggest that increased serotonergic activity may be involved in the induction of subsensitivity of the beta-adrenoceptor system of rat brain by sertraline.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2824215&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Reduction of feeding behavior by the serotonin uptake inhibitor sertraline.

Lucki I, Kreider MS, Simansky KJ.

Department of Psychiatry, University of Pennsylvania, Philadelphia 19104-4283.

Administration of the selective serotonin (5-HT) uptake inhibitor sertraline produced a dose-dependent reduction of food intake in rats. Doses of sertraline of 10 mg/kg or greater reduced the intake of solid pellets significantly (P less than 0.01) during the 1st hour of a 4-h feeding test in rats deprived of food and water for 24 h. Food intake during the remaining 3 h and water intake during the feeding test was unaffected by sertraline. Sertraline (2-18 mg/kg IP) also reduced milk consumption in food-deprived rats. Pretreatment with the nonselective 5-HT antagonists metergoline (2 mg/kg IP) or methysergide (3.3 mg/kg IP) blocked sertraline's inhibition of dry food intake, whereas pretreatment with the selective 5-HT2 receptor antagonist ketanserin (3.3 mg/kg IP) or the peripheral 5-HT2 antagonist xylamidine (2.5 mg/kg IP) failed to block sertraline's anorexic effect. The feeding-suppressant effect of 10 mg/kg sertraline was prevented following the destruction of central 5-HT neurons by the 5-HT neurotoxic agent, 5,7-dihydroxytryptamine (200 micrograms ICV). This result is consistent with sertraline's anorexic effect depending on intact 5-HT neurotransmission. Therefore, sertraline appears to reduce feeding by enhancing the action of endogenous serotonin at central synapses mediated by 5-HT1 rather than 5-HT2 receptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3146763&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Treatment with sertraline, a new serotonin uptake inhibitor, reduces voluntary ethanol consumption in rats.

Gill K, Amit Z, Koe BK.

Centre for Studies in Behavioral Neurobiology, Concordia University, Montreal, Quebec, Canada.

Serotonin uptake blockers have been shown to produce a robust and reliable reduction in voluntary ethanol consumption in rats. These compounds are currently under investigation as potential treatments for alcohol abuse in humans. It is uncertain whether serotonin uptake blockers exert their effects directly through serotonergic mechanisms or whether an interaction between the serotonin and noradrenergic systems is involved. The present series of experiments was designed to examine the effects of sertraline, a new selective serotonin uptake blocker, on voluntary ethanol intake. Sertraline produced a robust reduction in voluntary ethanol intake. It appears therefore, that increasing selectivity for serotonin blockade does not alter the efficacy of these compounds as antialcohol agents. The drug also reduced the consumption of a saccharin solution indicating that sertraline's effects are not specific to ethanol intake.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3219181&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
A further examination of the effects of sertraline on voluntary ethanol consumption.

Gill K, Filion Y, Amit Z.

Centre for Studies in Behavioral Neurobiology, Concordia University, Montreal, Canada.

Previous work with the serotonin uptake blocker, sertraline, demonstrated that the drug suppressed the consumption of ethanol and saccharin as well as body weight gain. There is increasing evidence that many serotonergic agents such as agonists, releasing agents and uptake blockers, reduce food intake. Sertraline was found to have a robust anorexic action. In this paper evidence is presented which supports the hypothesis that the administration of serotonin uptake blockers reduce ethanol consumption as a secondary consequence of a suppression in food intake.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3219182&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
The chronic effects of desipramine and sertraline on platelet and synaptosomal 5HT uptake in olfactory bulbectomised rats.

Butler J, Tannian M, Leonard BE.

Department of Pharmacology, University College, Galway, Republic of Ireland.

1. Depressed patients show a characteristic decrease in the rate of uptake of serotonin into their platelets, which is normalised only by clinically effective antidepressant treatment. 2. We also find a decrease in platelet 5HT uptake rates in the olfactory bulbectomised (OB) rat model of depression, which return to normal following three weeks of treatment with desipramine or sertraline. 3. Synaptosomal 5HT uptake appears to consist of a low affinity, high capacity component and a high affinity, low capacity component, both of which are increased in the OB rat, compared to its sham operated control, and normalised by chronic antidepressant treatment. 4. The low affinity uptake of serotonin is not inhibited by in vitro incubation with sertraline, which suggests that the low affinity system may be associated with a non-specific uptake of 5HT into noradrenergic or dopaminergic nerve endings.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3222448&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
The platelet serotonergic system in depression and following sertraline treatment.

Butler J, Leonard BE.

Department of Pharmacology, University College Galway, Republic of Ireland.

This preliminary study examined the effect of 8 weeks' treatment with the serotonin (5HT) uptake inhibitor, sertraline, on the platelet serotonergic system in depression. Patient pre-treatment platelet 5HT uptake rates and 5HT-mediated platelet aggregation responses were significantly reduced compared to the control values. Binding of the tritiated 5HT2 receptor antagonist, 3H-ketanserin, to platelet membranes from the patient group was increased above control levels. All the patients in the study had recovered from the depressive episode, assessed using the Hamilton depression rating scale, following 8 weeks' sertraline treatment. Eight weeks' sertraline treatment also resulted in a normalization of the biochemical parameters examined. Therefore, we conclude that sertraline is an effective antidepressant and these results confirm previous reports of abnormal platelet serotonin transport and aggregation response as putative markers of the depressed state.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3235819&dopt=Abstract sertraline Zoloft