Glucocorticoids Inhibit Stress-Induced Phosphorylation of CREB in Corticotropin-Releasing Hormone Neurons of the Hypothalamic Paraventricular Nucleus

Légràdi, Gábor; Holzer, David; Kapcala, Leonard P.; Lechan, Ronald M.

doi:10.1159/000127224

Cited by 62 publications

(33 citation statements)

References 28 publications

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“…In line with our previous data, a cAMP/PKA pathway activator, forskolin, about three-fold enhanced CRH-CAT activity in differentiated Neuro-2A cells (Budziszewska et al, 2004), while in another cell line a much larger increase was observed (Seasholtz et al, 1988). Furthermore, it has been found that stress-induced CRH synthesis in the hypothalamic neurons is most probably evoked by cAMP-PKA pathway activation, and in consequence the increased phosphorylation of CREB (Legradi et al, 1997). Since forskolin-stimulated CRH activity was inhibited by clozapine, chlorpromazine, haloperidol, and thioridazine, it can be expected that these drugs should also inhibit stress-stimulated CRH synthesis.…”

Section: Discussionsupporting

confidence: 91%

Antipsychotic Drugs Inhibit the Human Corticotropin-Releasing-Hormone Gene Promoter Activity in Neuro-2A Cells—an Involvement of Protein Kinases

Basta‐Kaim

Budziszewska

Jaworska-Feil

et al. 2005

Neuropsychopharmacol

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Antipsychotic drugs can regulate transcription of some genes, including those involved in regulation of hypothalamic-pituitary-adrenal (HPA) axis, whose activity is frequently disturbed in schizophrenic patients. However, molecular mechanism of antipsychotic drug action on the corticotropin-releasing hormone (CRH) gene activity has not been investigated so far. This study was undertaken to examine the influence of conventional and atypical antipsychotic drugs on the CRH gene promoter activity in differentiated Neuro-2A cell cultures stably transfected with a human CRH promoter fragment linked to the chloramphenicol acetyltransferase (CAT) reporter gene. It has been found that chlorpromazine (0.1-5.0 mM), haloperidol (0.5-5.0 mM), clozapine (1.0-5.0 mM), thioridazine (1.0-5.0 mM), promazine (5.0 and 10 mM), risperidone (5.0 and 10.0 mM), and raclopride (only at the highest used concentrations, ie 30 and 100 mM) present in culture medium for 5 days inhibited the CRH-CAT activity. Sulpiride and remoxipride had no effect. Since CRH gene activity is most potently enhanced by cAMP/protein kinase A pathway, the effect of antipsychotics on the forskolin-induced CRH-CAT activity was determined. Chlorpromazine (1.0-5.0 mM), haloperidol (1.0-5.0 mM), clozapine (1.0-5.0 mM), thioridazine (3.0 and 5.0 mM), and raclopride (30 and 100 mM), but not promazine, sulpiride, risperidone, and remoxipride, inhibited the forskolin-stimulated CRH gene promoter activity. A possible involvement of protein kinases in chlorpromazine and clozapine inhibitory action on CRH activity was also investigated. It was found that wortmannin (0.01 and 0.02 mM), an inhibitor of phosphatidylinositol 3-kinase (PI3-K), significantly attenuated the inhibitory effect of chlorpromazine and clozapine on CRH gene promoter activity. In line with these results, a Western blot study showed that these drugs increased phospho-Ser-473 Akt level, had no effect on total Akt, and decreased glycogen synthase kinase-3b level. Additionally, we found that clozapine decreased protein kinase C (PKC) level and that its action on CRH activity was attenuated by PKC activator (TPA, 0.1 mM). The obtained results indicate that inhibition of CRH gene promoter activity by some antipsychotic drugs may be a molecular mechanism responsible for their inhibitory action on HPA axis activity. Clozapine and chlorpromazine action on CRH activity operates mainly through activation of the PI3-K/Akt pathway. Moreover, PKC-mediated pathway seems to be involved in clozapine action on CRH gene activity.

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Section: Discussionsupporting

confidence: 91%

Antipsychotic Drugs Inhibit the Human Corticotropin-Releasing-Hormone Gene Promoter Activity in Neuro-2A Cells—an Involvement of Protein Kinases

Basta‐Kaim

Budziszewska

Jaworska-Feil

et al. 2005

Neuropsychopharmacol

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“…GR prevents CREB phosphorylation by direct linking to the protein and hindering its binding to CRE. In addition, glucocorticoids can directly affect CREB function by interfering with the phosphorylation of CREB (Legradi et al 1997). A significant difference in GR number and function in various cerebral areas characterize the transgenic mice used in this study, in the absence of significant elevations in peripheral corticosterone.…”

Section: Discussionmentioning

confidence: 97%

Altered Regulation of CREB by Chronic Antidepressant Administration in the Brain of Transgenic Mice with Impaired Glucocorticoid Receptor Function

Blom

Tascedda

Carra

et al. 2002

Neuropsychopharmacology

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Various effects of antidepressant drugs on gene transcription have been described and altered gene expression has been proposed as being a common biological basis underlying depressive illness. One target for the common action of antidepressants is a modifying effect on the regulation of postreceptor pathways and genes related to the cAMP cascade. Recent studies have demonstrated that long-term antidepressant treatment resulted in sustained activation of the cyclic adenosine 3 Ј ,5 Ј -monophosphate system and in increased expression of the transcription factor cAMP response element binding protein (CREB). KEY WORDS : CREB; Antidepressant drugs; Glucocorticoid receptor; Transgenic miceWhile the regulation of monoamine levels and their receptors or the restoration of hypothalamus-pituitaryadrenal (HPA) system feedback may represent initial effects of antidepressant drugs, their therapeutic action could be related to subsequent action on genes involved in postreceptor mechanisms. One such postreceptor target that can be influenced by either 5HT or NE as well as by drugs that affect these systems is the nuclear transcription factor cAMP response element binding protein (CREB) (Montminy, et al. 1990;Meyer and Habener 1993;Nibuya et al. 1996;Duman et al. 1997Duman et al. , 1999Thome et al. 2000). A role for the cAMP cascade in the long-term ac- (Nestler et al. 1989) and that the activity of CREB is enhanced following its phosphorylation by PKA (Meyer and Habener 1993;Ghosh and Greenberg 1995). Furthermore, viral mediated over-expression of CREB in two animal models of depression produced an antidepressant effect and resulted in improved behavioral performance in both models (Chen et al. 2001).Based on the hypothesis that the apparent lack of sensitivity to corticosteroids observed in major depression is causally linked to the pathogenesis of depression (Holsboer and Barden 1996;Holsboer 2000;Pariante and Miller 2001) as well as to the therapeutic effectiveness of antidepressant drugs (Barden 1996), a transgenic animal model of neuroendocrine changes associated with depression was developed (Pepin et al. 1992a). Insertion into the mouse genome of a transgene expressing antisense RNA complementary to a fragment of the glucocorticoid receptor (GR) cDNA produced an animal with a defect in the neuronal glucocorticoid receptors that mediate the effects of high "stress" levels of glucocorticoids on the negative feedback of the HPA system. These transgenic mice displayed impaired endogenous GR function and were characterized by dysfunctional glucocorticoid inhibitory feedback and disturbed ACTH and corticosterone secretory responses Karanth et al. 1997;Dijkstra et al. 1998). Long-term treatment of the transgenic mice with antidepressant drugs caused an increase in GR gene expression and produced significant normalization of the HPA system hyperactivity through restoration of functional glucocorticoid inhibitory feedback (Pepin et al. 1992b;Barden et al. 1995;Barden et al. 1997).Because the second messenger cyclic AMP plays a...

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“…52 There are cAMP-response elements located in the CRF gene promoter and binding of CREB stimulates CRF gene expression. 27 In vitro, glucocorticoids inhibit the CRF promoter through cAMP-dependent activity. 53 However, in our study, a change in CREB mRNA to accompany the increase of CRF mRNA expression in the PVN in depression was not found, so that our data do not provide support for a central role of CREB in the PVN in mood disorders.…”

Section: Crf Neurons and Crfr1 And Crfr2 Imbalancementioning

confidence: 99%

“…Alternatively, CRF gene regulation by CREB might not be attributed to different expression levels of CREB mRNA but to protein levels of phosphorylated CREB, which has been studied both in vitro and in vivo. 27,54 GR and MR imbalance The glucocorticoid feedback on the HPA axis is mediated by two types of receptors, GR and MR that have a different localization in the brain. 16 In depression, a downregulation of these receptors, secondary to the persistent hypercortisolism was presumed.…”

Section: Crf Neurons and Crfr1 And Crfr2 Imbalancementioning

confidence: 99%

Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances

et al. 2008

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Hyperactivity of corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN) of the hypothalamus is a prominent feature in depression and may be important in the etiology of this disease. The activity of the CRF neurons in the stress response is modulated by a number of factors that stimulate or inhibit CRF expression, including (1) corticosteroid receptors and their chaperones, heat shock proteins 70 and 90, (2) sex hormone receptors, (3) CRF receptors 1 (CRFR1) and 2, (4) cytokines interleukin 1-b and tumor necrosis factor-a, (5) neuropeptides and receptors, vasopressin (AVP), AVP receptor 1a (AVPR1A) and oxytocin and (6) transcription factor cAMP-response element-binding protein. We hypothesized that, in depression, the transcript levels of those genes that are involved in the activation of the hypothalamo-pituitary-adrenal (HPA) axis are upregulated, whereas the transcript levels of the genes involved in the inhibition of the HPA axis are downregulated. We performed laser microdissection and real-time PCR in the PVN and as a control in the supraoptic nucleus. Snap-frozen post-mortem hypothalami of seven depressed and seven matched controls were used. We found significantly increased CRF mRNA levels in the PVN of the depressed patients. This was accompanied by a significantly increased expression of four genes that are involved in the activation of CRF neurons, that is, CRFR1, estrogen receptor-a, AVPR1A and mineralocorticoid receptor, while the expression of the androgen receptor mRNA involved in the inhibition of CRF neurons was decreased significantly. These findings raise the possibility that a disturbed balance in the production of receptors may contribute to the activation of the HPA axis in depression.

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Glucocorticoids Inhibit Stress-Induced Phosphorylation of CREB in Corticotropin-Releasing Hormone Neurons of the Hypothalamic Paraventricular Nucleus

Cited by 62 publications

References 28 publications

Antipsychotic Drugs Inhibit the Human Corticotropin-Releasing-Hormone Gene Promoter Activity in Neuro-2A Cells—an Involvement of Protein Kinases

Antipsychotic Drugs Inhibit the Human Corticotropin-Releasing-Hormone Gene Promoter Activity in Neuro-2A Cells—an Involvement of Protein Kinases

Altered Regulation of CREB by Chronic Antidepressant Administration in the Brain of Transgenic Mice with Impaired Glucocorticoid Receptor Function

Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances

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