Increased synaptic availability of norepinephrine following desipramine is not essential for increases in GR mRNA

Eiring, A.; Sulser, Fridolin

doi:10.1007/bf01294725

Cited by 18 publications

(6 citation statements)

References 7 publications

(8 reference statements)

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“…*P Ͻ 0.005 resulted in a significantly reduced dark-induced NE mediated formation of melatonin (Heydorn et al, 1982) and a reduction in N-acetyltransferase activity (Friedman et al, 1984) despite the persistent increase in synaptic NE caused by either blockade of NE reuptake or inhibition of MAO. An agonistreceptor cascade -independent regulation of gene expression by antidepressants has been reported in brain in vivo (Rossby et al, 1995;Eiring and Sulser, 1997) and in transfected LTK-or neuroblastoma cells in vitro (Pepin et al, 1992). In the present studies, we demonstrate that DMI and reboxetine, but not venlafaxine, down-regulate isoproterenol stimulated nuclear CREB and CREB-P in human fibroblasts in vitro.…”

Section: Discussionmentioning

confidence: 95%

Noradrenergic antidepressants: does chronic treatment increase or decrease nuclear CREB-P?

Manier

Shelton

Sulser

2002

Journal of Neural Transmission

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Chronic administration of noradrenergic antidepressants causes a desensitization of the beta adrenoceptor coupled adenylate cyclase system. In the present studies, we attempted to answer the question of whether or not this deamplification is reflected beyond the second messenger system. Nuclear CREB-P was determined in frontal cortex of rats following acute and chronic administration of desipramine (DMI) or reboxetine and in human fibroblasts following incubation for 48 hours with DMI, reboxetine or venlafaxine. Nuclear CREB-P in the frontal cortex was significantly decreased following chronic administration of DMI or reboxetine. Moreover, incubation of human fibroblasts with DMI or reboxetine, but not with venlafaxine, caused a highly significant reduction in nuclear CREB-P suggesting that the noradrenergic antidepressants exert direct effects beyond beta adrenoceptors. The results are consistent with the view that chronic treatment with antidepressants causes a net deamplification of the norepinephrine mediated signal transduction cascade which might "normalize" the increased noradrenergic activity evident in major depression.

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Section: Discussionmentioning

confidence: 95%

Noradrenergic antidepressants: does chronic treatment increase or decrease nuclear CREB-P?

Manier

Shelton

Sulser

2002

Journal of Neural Transmission

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“…Interestingly, the relationship between the chemical structure of an antidepressant, the known pharmacological mechanism and the effects on the GR has yet to be clarified, although the inhibition of catecholamine uptake – the mechanism currently believed to be crucial in the antidepressant action of these drugs – seems not relevant (Pariante & Miller, 2001). For example, in animal studies, GR upregulation in the brain is induced by tricyclics (Eiring & Sulser, 1997; Reul et al ., 1993; Rossby et al ., 1995; Seckl & Fink, 1992) but not by SSRIs (Seckl & Fink, 1992). Moreover, the noradrenaline reuptake inhibitor, oxaprotiline, has shown no effects on GR expression (Eiring & Sulser, 1997), and desipramine has been shown to induce GR upregulation even following neurotoxic lesioning of noradrenergic neurons with DSP4 (Rossby et al ., 1995).…”

Section: Discussionmentioning

confidence: 99%

Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters

Pariante

Makoff

Lovestone

et al. 2001

British J Pharmacology

152

144

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Previous data demonstrate that the tricyclic antidepressant, desipramine, induces glucocorticoid receptor (GR) translocation from the cytoplasm to the nucleus in L929 cells and increases dexamethasone‐induced GR‐mediated gene transcription in L929 cells stably transfected with the mouse mammary tumour virus‐chloramphenicol acetyltransferase (MMTV‐CAT) reporter gene (LMCAT cells) (Pariante et al., 1997). To extend these findings, the present study has investigated the effects of 24 h coincubation of LMCAT cells with dexamethasone and amitriptyline, clomipramine, paroxetine, citalopram or fluoxetine. All antidepressants, except fluoxetine, enhanced GR‐mediated gene transcription, with clomipramine having the greatest effect (10 fold increase). Twenty‐four hours coincubation of cells with desipramine, clomipramine or paroxetine, also enhanced GR function in the presence of cortisol, but not of corticosterone. It is proposed that these effects are due to the antidepressants inhibiting the L929 membrane steroid transporter, which actively extrudes dexamethasone and cortisol from the cell, but not corticosterone. This is further confirmed by the fact that clomipramine failed to enhance GR‐mediated gene transcription in the presence of dexamethasone when the membrane steroid transporter was blocked by verapamil. The membrane steroid transporters that regulate access of glucocorticoids to the brain in vivo, like the multiple drug resistance p‐glycoprotein, could be a fundamental target for antidepressant action. British Journal of Pharmacology (2001) 134, 1335–1343; doi:

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“…Inasmuch as BDNF can be regulated by other mechanisms than cAMP-CREB, corticosteroids can also be functionally regulated by antidepressants in the absence of adrenoceptors. Pepin and coworkers (1992) have demonstrated increased GR promoter activity in fibroblast cells that are devoid of aminergic receptors, and other studies (Rossby et al 1995;Eiring and Sulser 1997) found that increased hippocampal GR mRNA expression is independent of increased adrenoceptor stimulation and, in general, independent of norepinephrine bioavailability. In this context, another interesting aspect that has been introduced by Pariante et al (1997), is that GR trafficking can be induced by antidepressants independently of ligand binding and receptor activation, thus pointing to an interaction of antidepressants with chaperones, and an interference with the energy supply (ATP) necessary to maintain corticosteroid receptors in a hormone-binding mode through energyrequiring activities of chaperones.…”

Section: Consequences For Future Drug Treatment Of Depression Currentmentioning

confidence: 97%

The Corticosteroid Receptor Hypothesis of Depression

Holsboer

2000

Neuropsychopharmacology

1,984

1,228

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Clinical EvidenceUntil now, the serendipitous discovery of antidepressants in the 1950s has profoundly inspired hypotheses of the pathogenesis of depression. The well-known pharmacological effects of antidepressants on presynaptic uptake transporters and degradating enzymes (i.e., MAO) of serotonin and norepinephrine has focused research on causality and treatment of depression on the metabolism of functional biogenic amines and the capacity of their respective receptors to alter intracellular signaling pathways that ultimately induce changes in gene activity. Elevated circulating levels of stress hormones among depressives were recognized even before antidepressants were discovered, but these changes were seen as epiphenomena, reflecting the stressful experience of depression, although M. Bleuler (1919) already demonstrated that hormones have diverse psychotropic effects and suggested hormone treatments as potential antidepressants. A vast amount of evidence has accumulated, that reject the view that altered stress hormone secretions in depression are epiphenomenal. During the past decade, several research groups formulated a hypothesis relating aberrant stress hormone dysregulation to causality of depression and submitted that antidepressants may act through normalisation of these HPA changes (

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Increased synaptic availability of norepinephrine following desipramine is not essential for increases in GR mRNA

Cited by 18 publications

References 7 publications

Noradrenergic antidepressants: does chronic treatment increase or decrease nuclear CREB-P?

Noradrenergic antidepressants: does chronic treatment increase or decrease nuclear CREB-P?

Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters

The Corticosteroid Receptor Hypothesis of Depression

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