Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system.

Reul, Johannes M. H. M.; Stec, I.; Söder, M.; Holsboer, Florian

doi:10.1210/endo.133.1.8391426

Cited by 235 publications

(103 citation statements)

References 38 publications

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“…Moreover, chronic treatment with fluoxetine, as well as other antidepressants, significantly elevated the levels of glucocorticoid receptors in the hippocampus (Brady et al 1991(Brady et al , 1992, which normally mediate the negative feedback response to stress-induced activation of the HPA axis (Sapolsky et al 1984). Finally, our results are in agreement with previous studies in experimental animals (Reul et al 1993) and in healthy humans (Michelson et al 1997), which reported that chronic treatment with antidepressants markedly attenuated the pituitary-adrenal response to stressful or pharmacological challenges. Although the role of CRH in mediating the anorexic effects of LPS has not been studied directly, there are indications that CRH mediates the anorexic effects of IL-1 (Bluthe et al 1992;Uehara et al 1989).…”

Section: Discussionsupporting

confidence: 92%

Effects of Antidepressant Drugs on the Behavioral and Physiological Responses to Lipopolysaccharide (LPS) in Rodents

Yirmiya

Pollak

Barak

et al. 2001

Neuropsychopharmacology

203

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Antidepressants produce various immunomodulatory effects, as well as an attenuation of the behavioral responses to immune challenges, such as lipopolysaccharide (LPS). To explore further the effects of antidepressants on neuroimmune interactions, rats were treated daily with either fluoxetine (Prozac) or saline for 5 weeks, and various behavioral, neuroendocrine, and immune functions were measured following administration of either LPS or saline. Chronic fluoxetine treatment significantly attenuated the anorexia and body weight loss, as well as the depletion of CRH-41 from the median eminence and the elevation in serum corticosterone levels induced by LPS. Chronic treatment with imipramine also attenuated LPS-induced adrenocortical activation. In rats and in mice, which normally display a biphasic body temperature response to LPS (initial hypothermia followed by hyperthermia), chronic treatment with fluoxetine completely abolished the hypothermic response and facilitated and strengthened the hyperthermic response. The effects of antidepressants on the responsiveness to LPS are probably not mediated by their effects on peripheral proinflammatory cytokine production, because LPS-induced expression of TNFSeveral lines of evidence indicate that antidepressants produce various immunomodulatory effects. In depressed patients, the effects of antidepressants are variable and seem to be related to the immune status of the patients at the initiation of the treatment. When depression was associated with immune activation, antidepressants reduced immune function and cytokine secretion. For example, the increased plasma levels of IL-6 during acute depression were normalized by 8-week treatment with fluoxetine (Sluzewska et al. 1995), the increased monocyte counts in depressed patients were reduced following 6-weeks treatment with tricyclic antidepressants (TCAs) (Seidel et al. 1996), and the increased numbers of leukocytes and neutrophils were also reduced by antidepressant treatment (Maes et al. 24 , NO . 5 1997). On the other hand, when immune functions were found to be normal, antidepressants had no immunological effects; for example, chronic moclobemide treatment had no effect on monocytes functions, TNF ␣ production or IFN ␥ levels (Landmann et al. 1997). Moreover, in a study of depressed patients who exhibited immune suppression before treatment, the TCA clomipramine increased the production of IL-1 ␤ , IL-2, and IL-3 (Weizman et al. 1994).In experimental animals, TCAs as well as selective serotonin reuptake inhibitors (SSRIs) produce mainly immune suppression and anti-inflammatory effects. For example, antidepressant treatment in vivo inhibited the increased acute phase response in olfactory bulbectomized rats, a useful animal model of depression (Song and Leonard 1994), reduced the production of interleukin-1 (IL-1) and IL-2 in a chronic mild stress model of depression (Kubera et al. 1996), inhibited immune activation in rats with experimental allergic neuritis (Zhu et al. 1994), and produced anti-inflammatory ...

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Section: Discussionsupporting

confidence: 92%

Effects of Antidepressant Drugs on the Behavioral and Physiological Responses to Lipopolysaccharide (LPS) in Rodents

Yirmiya

Pollak

Barak

et al. 2001

Neuropsychopharmacology

203

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“…Our preferred model is that desipramine initially increases hippocampal GR translocation and function in both mice groups; the increased GR translocation and function lead to both the reduced corticosterone levels (following enhanced negative feedback) and the GR downregulation (following GR internalization into cellular nuclei). This model is supported by studies in rats, where antidepressants decrease HPA axis activity and induce GR downregulation within the first few days of treatment (Reul et al, 1993;Yau et al, 2001), and by studies in vitro, where antidepressants induce GR translocation and GR downregulation within one or 2 days of treatment (Pariante et al, 1997(Pariante et al, , 2003aOkugawa et al, 1999;Yau et al, 2001;Heiske et al, 2003). Indeed, Mukherjee et al (2004) found that one single dose of imipramine in mice induces GR translocation in the CA1 subregion, the same area where we find the GR downregulation.…”

Section: Discussionsupporting

confidence: 82%

“…Nevertheless, even if brain levels of desipramine were increased in abcb1ab (À/À) mice, there is no evidence that higher doses of tricyclic could lead to hippocampal GR downregulation rather than upregulation. In fact, one study in rats treated with amitriptyline (for 5 weeks) have found no evidence of hippocampal GR downregulation even using a dose that was 15-fold larger than the minimal dose able to induce GR upregulation (Reul et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice

Yau

Noble

Thomas

et al. 2007

Neuropsychopharmacol

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The mechanisms by which antidepressants regulate the hypothalamic-pituitary-adrenal (HPA) axis are still unknown. The ABCB1-type multiple drug resistance (MDR) p-glycoprotein (PGP) regulates the HPA axis by limiting the access of glucocorticoids to the brain in mice and humans. Previous work in cell cultures has found that antidepressants enhance glucocorticoid receptor (GR) function in vitro by inhibiting MDR PGP, and therefore by increasing the intracellular concentration of glucocorticoidsFbut this model has never been tested directly in animals. Here, the tricyclic antidepressant, desipramine (20 mg/kg/day, i.p., for seven days), was administered to abcb1ab MDR PGP knockout mice (congenic on the FVB/N background strain) and to FVB/N controls. The hippocampal mRNA expression of GR, mineralocorticoid receptor (MR), MDR (Mdr1a) PGP, and 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) were measured, together with plasma corticosterone levels. In FVB/N controls, desipramine induced a significant upregulation of GR mRNA in the CA1 region ( + 31%; p ¼ 0.045); in contrast, in abcb1ab (À/À) mice, desipramine induced a significant downregulation of GR mRNA in the CA1 region (À45%; p ¼ 0.004). MR mRNA expression was unaltered. Desipramine decreased corticosterone levels in both FVB/N controls and in abcb1ab (À/À) mice, but in abcb1ab (À/À) mice the effects were smaller. Specifically, in FVB/N controls (but not in abcb1ab (À/À) mice), desipramine reduced corticosterone levels not only compared with saline-treated mice but also compared with the 'physiological' levels of untreated mice (À39%; p ¼ 0.05). Finally, desipramine reduced Mdr1a mRNA expression across all hippocampus areas (À9 to À23%), but had no effect on 11b-HSD1 mRNA expression. These data support the notion that the MDR PGP is one of the molecular targets through which antidepressants regulate the HPA axis.

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“…Brains were rapidly removed from the skull, the hippocampus and hypothalamus were dissected and the anterior pituitary was collected. Dissected tissues were instantaneously frozen in liquid N 2 and stored at Ϫ80ЊC until corticosteroid receptor assay as described elsewhere (Reul et al 1993 …”

Section: Adrenalectomy Tissue Collection and [ 3 H]-steroid Binding mentioning

confidence: 99%

“…In a separate set of experiments, the MR and GR concentrations were assessed by a soluble corticosteroid binding assay (Reul and de Kloet 1985;Reul et al 1993). For the corticosteroid binding experiments, male HAB (n ϭ 11) and LAB (n ϭ 10) rats were bilaterally adrenalectomized (ADX; via the dorsal approach under halothane anesthesia) between 7 A.M. and noon, i.e.…”

Section: Adrenalectomy Tissue Collection and [ 3 H]-steroid Binding mentioning

confidence: 99%

Vasopressin Mediates the Response of the Combined Dexamethasone/CRH Test in Hyper-anxious Rats Implications for Pathogenesis of Affective Disorders

Keck

Wigger

Welt

et al. 2002

Neuropsychopharmacology

157

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To investigate the neuroendocrine alterations linked to inborn emotionality in two Wistar rat lines selectively bred for either high (HAB) or low (LAB) anxiety-related behavior, we administered the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH)testNeuroendocrine studies provide strong indications that hyperactivity of central corticotropin-releasing hormone (CRH) circuits, resulting in a characteristic dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system, plays a causal role in the symptomatology of affective and anxiety disorders (review: Keck and Holsboer 2001). The effects of CRH are modulated by vasopressin (AVP), which, after prolonged stress and in senescence, is increasingly coexpressed and secreted from hypothalamic CRH neurons in both humans and rodents (Antoni 1993;Tilders et al. 1993;Hatzinger et al. 2000;Keck et al. 2000). Similarly, increased numbers of CRH neurons that coexpress AVP mRNA have been found in the hypothalamus of depressed patients (Raadsheer et al. 1993;Purba et al. 1996). The excessive release of CRH and AVP into hypophysial portal blood is thought to increase the secretion of corticotropin (ACTH) from pituitary corticotrope cells, and this in turn to increase the release of corticosteroids from the adrenal gland. In this context, a variety of changes in HPA system regulation have been demonstrated in psychiatric disorders such as major depression, among them defective negative feedback of the HPA system, basal hypercortisolemia, inappropriate HPA suppression by the synthetic corticosteroid dexamethasone (DEX) and a paradoxical stimulation of ACTH secretion by CRH after DEX pretreatment (review: Holsboer and Barden 1996;Holsboer 2000). In depression, the combined DEX/CRH test, in which DEX-pretreated subjects receive a single dose of CRH, has proven to be the most sensitive tool for the detection of altered HPA regulation. Depending on age and gender, up to 90% of patients with depression show this neuroendocrine phenomenon (Heuser et al. 1994). Moreover, studies using the DEX/CRH test not only agree that normalization of an initial aberrance is predictive of a favorable treatment response but also corroborate other evidence that a persistent HPA abnormality correlates with chronicity or relapse (Heuser et al. 1996;Zobel et al. 1999). Since activation of corticosteroid receptors suppresses the synthesis and release of CRH and AVP from the hypothalamic paraventricular nucleus (PVN) , these findings are consistent with the hypothesis of functionally impaired corticosteroid receptor signaling in both depressed patients (Modell et al. 1997) and healthy subjects at genetic risk for depression Modell et al. 1998).As the mechanisms underlying the abnormal HPA reactivity in patients with certain psychiatric disorders are not fully understood, animal models are needed to further investigate the hypothesized linkage between these disorders and changes in the regulation of the HPA system. After several generations of selective breeding, we could establish ...

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Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system.

Cited by 235 publications

References 38 publications

Effects of Antidepressant Drugs on the Behavioral and Physiological Responses to Lipopolysaccharide (LPS) in Rodents

Effects of Antidepressant Drugs on the Behavioral and Physiological Responses to Lipopolysaccharide (LPS) in Rodents

The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice

Vasopressin Mediates the Response of the Combined Dexamethasone/CRH Test in Hyper-anxious Rats Implications for Pathogenesis of Affective Disorders

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