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

Abstract

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...

The Antidepressant Clomipramine Regulates Cortisol Intracellular Concentrations and Glucocorticoid Receptor Expression in Fibroblasts and Rat Primary Neurones

“…Data showing that PGP inhibitors induce partial GR translocation support this possibility (Prima et al, 2000). Antidepressants could also induce GR translocation through their effect on cAMP-dependent protein kinases (Rangarajan et al, 1992;Chen and Rasenick, 1995;Miller et al, 2002;Blom et al, 2002). Translocation of GR, in turn, could lead to the reduction in GR expression.…”

cAMP Response Element-Binding Protein Deficiency Allows for Increased Neurogenesis and a Rapid Onset of Antidepressant Response

“…Chronic exposure to AD is accompanied by transcriptional and cellular modulation, occurring on a later timescale than changes in monoamine levels and consistent with the onset of the relief of symptoms (Frazer and Benmansour, 2002;Nestler et al, 2002;Young et al, 2002;Carlezon et al, 2005;Blendy, 2006). In particular, the transcription factor cAMP response element-binding protein (CREB) is upregulated after chronic AD treatment; increases in CREB mRNA and protein, or phosphorylation of CREB have been shown in the hippocampus after chronic, but not acute AD administration (Nibuya et al, 1996;Thome et al, 2000;Blom et al, 2002;Tiraboschi et al, 2004).…”

Signaling Pathways Regulating Gene Expression, Neuroplasticity, and Neurotrophic Mechanisms in the Action of Antidepressants: A Critical Overview

“…CREB expression was investigated following chronic treatment with FLX or DMI of mice with impaired glucocorticoid receptor function. Whereas in wild-type (wt) mice both drugs increased expression in hippocampus but not in cerebral cortex, in transgenic (tr) mice FLX increased expression in hippocampus, and both drugs did so in cerebral cortex (Blom et al, 2002). These results on the regulation of CREB by antidepressants were complemented by data from postmortem brain analysis, showing that the level of CREB protein was higher in the temporal cortex of depressed patients treated with antidepressants at the time of death than in temporal cortex of untreated patients (Dowlatshahi et al, 1998) and that mRNA and protein CREB levels as well as CRE-binding activity were significantly reduced in brains from suicide subjects (Dwivedi et al, 2003).…”