sertraline, Zoloft
Effects of reboxetine and sertraline treatments alone and in combination on the binding properties of cortical NMDA and beta1-adrenergic receptors in an animal model of depression.

Harkin A, Nally R, Kelly JP, Leonard BE.

Department of Pharmacology, National University of Ireland, Galway. andrew.harkin nuigalway.ie

Changes to the binding properties of cortical N-methyl-D-aspartic acid (NMDA) and beta-adrenergic receptors have both been reported as potential indicators of antidepressant activity. In the present investigation we examined the effects of the noradrenaline reuptake inhibitor, reboxetine, the serotonin reuptake inhibitor, sertraline, alone and in combination on the binding properties of cortical NMDA receptors and cortical beta1-adrenoceptors following 14 days of treatment in the olfactory bulbectomized rat model of depression. A decrease in the potency of glycine to displace the strychnine insensitive glycine antagonist [3H] 5,7 dichlorokynurenic acid (5,7 DCKA) was observed in cortical homogenates of OB rats when compared to sham-operated controls. Similarly, treatment with the combination of reboxetine and sertraline for 14 days produced a decrease in the potency of glycine when compared to vehicle treated controls. By contrast neither olfactory bulbectomy or drug treatment significantly altered basal or glycine enhanced binding of the non-competitive NMDA antagonist [3H] MK-801 in cortical homogenates. Reboxetine alone, and in combination with sertraline, down-regulated [3H]-CGP 12177 (a selective beta-adrenoceptor antagonist) binding in both OB and sham-operated animals. The lack of a bulbectomy effect in the [3H] CGP-12177 binding assay, and the fact that olfactory bulbectomy and antidepressant treatments produce a similar change to the potency of glycine at the NMDA receptor, suggests that these tests do not provide a neurochemical marker for either the behavioral hyperactivity deficit or antidepressant response in the model.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11129111&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Acute effect of different antidepressants on glycemia in diabetic and non-diabetic rats.

Gomez R, Huber J, Tombini G, Barros HM.

Divisao de Farmacologia, Fundacao Faculdade Federal de Ciencias Medicas de Porto Alegre, Porto Alegre, RS, Brasil.

Diabetic patients have a 20% higher risk of depression than the general population. Treatment with antidepressant drugs can directly interfere with blood glucose levels or may interact with hypoglycemic agents. The treatment of depression in diabetic patients must take into account variations of glycemic levels at different times and a comparison of the available antidepressant agents is important. In the present study we evaluated the interference of antidepressants with blood glucose levels of diabetic and non-diabetic rats. In a first experiment, male adult Wistar rats were fasted for 12 h. Imipramine (5 mg/kg), moclobemide (30 mg/kg), clonazepam (0.25 mg/kg), fluoxetine (20 mg/kg) sertraline (30 mg/kg) or vehicle was administered. After 30 min, fasting glycemia was measured. An oral glucose overload of 1 ml of a 50% glucose solution was given to rats and blood glucose was determined after 30, 60 and 90 min. Imipramine and clonazepam did not change fasting or overload glycemia. Fluoxetine and moclobemide increased blood glucose at different times after the glucose overload. Sertraline neutralized the increase of glycemia induced by oral glucose overload. In the second experiment, non-diabetic and streptozotocin-induced diabetic rats were fasted, and the same procedures were followed for estimation of glucose tolerance 30 min after glucose overload. Again, sertraline neutralized the increase in glycemia after glucose overload both in diabetic and non-diabetic rats. These data raise the question of whether sertraline is the best choice for prolonged use for diabetic individuals, because of its antihyperglycemic effects. Clonazepam would be useful in cases with potential risk of hypoglycemia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11151029&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
[Comparison of the effects of the administration of fluoxetine and sertraline on the immune markers of the mu opioid receptor in the rat brain]

[Article in Spanish]

Acebes I, Echevarria E, Abecia LC, Barbero I, Maza JL, Casis L.

Departamento de Fisiologia, Facultad de Farmacia, Universidad del Pais Vasco, Vitoria-Gasteiz, Alava, Espana.

INTRODUCTION: Chronic fluoxetine or imipramine administration in rats can generate a similar increase in the number of neural cells immunostained for mu opioid receptors in several prosencephalic regions. OBJECTIVE: The aim of the present work was to describe the effects of chronic sertraline administration on mu opioid receptor immunostaining in several rat brain prosencephalic regions, in order to compare with previously described fluoxetine effects. MATERIALS AND METHODS: Experimental animals were chronically administered with sertraline (i.p.). An immunocytochemical method, with the aid of a computerized image analysis system, was used in order to measure the number of neural cells immunostained for mu opioid receptors in several prosencephalic regions. RESULTS: Although chronic sertraline administration in rats generates a significant increase in the number of neural cells immunostained for mu opioid receptors in the caudatus-putamen, dentate gyrus, lateral septum and the frontal, parietal and piriform cortices, slight regional differences, with respect to fluoxetine action, were found. Thus, a more marked action on parietal cortex and lateral septum, and a lesser action on the frontal cortex, were found. CONCLUSION: Regional differences in sertraline effects, with respect to fluoxetine, could be related to a lesser incidence of psychomotor impairment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11244683&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Inhibition of phenytoin hydroxylation in human liver microsomes by several selective serotonin re-uptake inhibitors.

Nelson MH, Birnbaum AK, Remmel RP.

Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 8-101 WDH, 308 Harvard Street, S.E., Minneapolis, MN 55455, USA.

Several case reports have indicated that the selective serotonin re-uptake inhibitor (SSRI) fluoxetine increases phenytoin blood levels when given concurrently. The mechanism of this drug-drug interaction has been attributed to inhibition of CYP2C9-catalyzed hydroxylation of phenytoin to its major oxidative metabolite in humans, para-hydroxyphenyl phenyl hydantoin (HPPH). With a bank of human liver microsomes (HLM), four SSRIs (fluoxetine, norfluoxetine, sertraline, and paroxetine) were tested for inhibition of HPPH formation. Initially, the K(m) and V(max) values of phenytoin hydroxylation to HPPH were determined in the individual HLM samples. The average K(m) (n=8) was 9.7+/-2.9 microM. The V(max) varied fivefold, with an average value of 113+/-53 pmol HPPH/min/nmol CYP450. All of the SSRIs inhibited HPPH formation; resulting Ki values were 31.1+/-10.1 microM (fluoxetine) (n=5), 51.1+/-9.4 microM (norfluoxetine) (n=3), 52.2+/-21.5 microM (sertraline) (n=3), and 80.0+/-7.2 microM (paroxetine) (n=3). Sulfaphenazole (10 microM), utilized as a positive control for inhibition of HPPH formation, inhibited phenytoin hydroxylation (>95%) in all HLM samples. Diclofenac hydroxylation to 4'-OH diclofenac, a specific marker for CYP2C9 activity, was determined in HLM1-HLM6 and was highly correlated with HPPH formation in HLM1-HLM6, indicating that phenytoin hydroxylation in human liver microsomes is largely due to CYP2C9. This work presents direct evidence that the effect of fluoxetine on phenytoin blood levels may be explained by inhibition of CYP2C9-catalyzed phenytoin hydroxylation. In light of typical SSRI blood levels observed in patients, this study also suggests that the risk of a SSRI-phenytoin interaction is highest with fluoxetine and norfluoxetine, and less likely with sertraline and paroxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11255075&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Prescribing patterns in patients using new antidepressants.

Meijer WE, Heerdink ER, Pepplinkhuizen LP, van Eijk JT, Leufkens HG.

Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht, The Netherlands.

AIMS: To study possible selective prescribing ('channelling') we compared characteristics of patients using the SSRI sertraline with patients using longer available SSRIs. METHODS: An observational cohort study in 1251 patients being prescribed an SSRI. RESULTS: In contrast to other studies, we found no evidence for channeling of sertraline. Sertraline was mainly prescribed for the labelled indication (depressive disorder), while older SSRIs were more often prescribed also for other indications. Time on the market was inversely associated to the proportion of patients treated for depressive disorder. CONCLUSIONS: We found no evidence for channeling of sertraline compared with prescribing patterns of older SSRIs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11259993&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Serotonin reverses dominant social status.

Larson ET, Summers CH.

Department of Biology and Neuroscience Group, University of South Dakota, 414 E. Clark Street, 57069-2390, Vermillion, SD, USA

Social stress from aggressive interaction is expressed differently in specific brain regions of dominant and subordinate male Anolis carolinensis. Prior to aggressive behavior, the outcome is predictable via the celerity of postorbital coloration: Dominant males exhibit more rapid eyespot darkening. Serotonergic activation is manifest rapidly (1 h) in hippocampus, nucleus accumbens and brainstem of subordinate males, and is expressed more rapidly in dominant males. Amygdalar serotonergic activation responds rapidly (1 h) in dominant males, but is expressed slowly (1 w) and chronically in subordinate males. We hypothesized that chronic (1 w) serotonin elevation, manipulated by the selective serotonin reuptake inhibitor sertraline, would decrease aggressiveness and result in subordinate status. Dominant status was established in pairs of male A. carolinensis. The pairs were separated and treated with sertraline or vehicle. Sertraline was given in food to either the dominant or the subordinate male, both males or neither male for 1 week. Pairs were reintroduced, and behavior and social status recorded. When both dominant and subordinate males were treated with sertraline (or vehicle), or when subordinate males alone were treated with sertraline, previously established social relationships remained unchanged or became associative. However, when dominant males alone were treated with sertraline, their social status was reversed (43%) or negated (57%). Latency to eyespot darkening was significantly retarded in dominant males treated with sertraline, and aggressive displays and attacks were reduced. Chronic 5-HT elevation is consistent with subordinate status. Social status and aggressive disposition do not appear to be immutable, but may be changed by neuroendocrine mechanisms that mediate adaptation to environmental conditions like stress.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11275287&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Morphine, cocaine and antidepressant induced motivational activity and midbrain dopaminergic neurotransmission.

Deslandes PN, Pache DM, Buckland P, Sewell RD.

Pharmacology Department, Welsh School of Pharmacy, Redwood Building, King Edward VII Avenue, CF10 3XF, Cardiff, UK.

Positive motivational properties of opioids, stimulants and serotonin selective reuptake inhibitors have been reported following place preference conditioning. The possibility that these effects are associated with changes in dopamine concentration in the nucleus accumbens or striatum was investigated. Male Wistar rats were place conditioned in a three compartment model to vehicle or drug (morphine 2.5 mg/kg, cocaine 5 mg/kg, sertraline 5 mg/kg or paroxetine 15 mg/kg) alternately for 8 days using a 30 min pre-treatment time. Control animals received saline only. Nucleus accumbens and striatal tissue were dissected 72 h after final drug dose, and the concentration of dopamine and its metabolites determined using high performance liquid chromatography (HPLC). Striatal dopamine D1-like receptor density was also determined through radioligand binding. Significant place preference (P<0.05) was observed with morphine, cocaine and sertraline. Morphine treated subjects showed a significant decrease (P<0.05) in striatal dopamine concentration, whilst cocaine and sertraline treatment resulted in a significant increase in striatal dopamine levels. Nucleus accumbens concentrations of dopamine, and striatal dopamine D1-like receptor density remained unchanged. The changes in striatal dopamine concentrations are consistent with withdrawal from opioid and stimulant compounds, and suggest that place preference conditioning may, in part, result from negative motivational or aversive effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12398908&dopt=Abstract sertraline Zoloft