Hypothalamic-Pituitary-Adrenocortical Axis Changes in the Rat after Long-Term Treatment with the Reversible Monoamine Oxidase-A Inhibitor Moclobemide

Reul, Johannes M. H. M.; Labeur, Marta; Grigoriadis, Dimitri E.; Souza, Errol B. De; Holsboer, Florian

doi:10.1159/000126788

Cited by 173 publications

(79 citation statements)

References 29 publications

(34 reference statements)

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“…In the light of the inhibitory effect of MRs on HPA activity which is reflected by studies employing MR antagonists in rats (Spencer et al 1998) and humans (Dodt et al 1993;Young et al 1998) or MR antisense in rats , the observed upregulation of MR capacity seems to be a first step necessary for the inhibition of hypothalamic CRH neurons. This effect on MR is followed by increased GR capacity (Brady et al 1991;Seckl and Fink 1992;Reul et al 1993Reul et al , 1994.…”

Section: Consequences For Future Drug Treatment Of Depression Currentmentioning

confidence: 95%

The Corticosteroid Receptor Hypothesis of Depression

Holsboer

2000

Neuropsychopharmacology

1,982

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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Section: Consequences For Future Drug Treatment Of Depression Currentmentioning

confidence: 95%

The Corticosteroid Receptor Hypothesis of Depression

Holsboer

2000

Neuropsychopharmacology

1,982

1,228

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“…Antidepressants increase mRNA levels of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR), and their hormone binding activities (Kitayama et al, 1988;Seckl and Fink, 1992;Reul et al, 1993Reul et al, , 1994. Also, GR promoter activity is increased by antidepressants, both in vitro (Pepin et al, 1992) and in vivo (Peiffer et al, 1991).…”

Section: Antidepressants and Bdnfmentioning

confidence: 99%

Antidepressants reverse corticosterone-mediated decrease in brain-derived neurotrophic factor expression: Differential regulation of specific exons by antidepressants and corticosterone

2006

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Earlier studies have implicated BDNF in stress and in the mechanism of action of antidepressants. It has been shown that antidepressants upregulate, whereas corticosterone downregulates, BDNF expression in rat brain. Whether various classes of antidepressants reverse corticosterone-mediated downregulation of BDNF is unclear. Also not known is how antidepressants or corticosterone regulate BDNF expression. To clarify this, we examined the effects of various classes of antidepressants and corticosterone, alone and in combination, on the mRNA expression of total BDNF and of individual BDNF exons, in rat brain. Normal or corticosterone pellet-implanted (100 mg, 21 days) rats were injected with different classes of antidepressants, fluoxetine, desipramine, or phenelzine, intraperitoneally for 21 days and sacrificed 2 h after the last injection. mRNA expression of total BDNF and of exons I-IV was measured in frontal cortex and hippocampus. Given to normal rats, fluoxetine increased total BDNF mRNA only in hippocampus, whereas desipramine or phenelzine increased BDNF mRNA in both frontal cortex and hippocampus. When specifc exons were examined, desipramine increased expression of exons I and III in both brain areas, whereas phenelzine increased exon I in both frontal cortex and hippocampus but exon IV only in hippocampus. On the other hand, fluoxetine increased only exon II in hippocampus. Corticosterone treatment of normal rats decreased expression of total BDNF mRNA in both brain areas, specifically decreasing exons II and IV. Treatment with desipramine or phenelzine of corticosterone pellet-implanted rats reversed the corticosterone-induced decrease in total BDNF expression in both brain areas; however, fluoxetine reversed the decrease only partially in hippocampus. Interestingly, antidepressant treatment of corticosterone pellet-implanted rats increased only those specific exons that are increased during treatment of normal rats with each particular antidepressant. We found that although corticosterone and antidepressants both modulate BDNF expression, and antidepressants reverse the corticosterone-induced BDNF decrease, antidepressants and corticosterone differ in how they regulate the expression of BDNF exon(s).

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“…Moreover, major depression is known to be frequently accompanied by frontal cortex dysfunction (Soares and Mann 1997;George et al 1999), whereby the frontal cortex is known to exert a regulatory role in HPA system activity (Diorio et al 1993). Findings of blunted hormone responses to stress have been obtained in rats after chronic treatment with various antidepressants (Reul et al 1993(Reul et al , 1994. Thus, since pharmacologically different drugs attenuate HPA system function, this neuroendocrine system was hypothesized to be a common denominator for clinically efficacious antidepressants (Holsboer and Barden 1996).…”

Section: Neuroendocrine Effects Of Rtms: Attenuation Of the Stress-inmentioning

confidence: 99%

“…In this context, HPA system function has been suggested as a common denominator for clinically effective antidepressant treatment strategies (Holsboer and Barden 1996). Indeed, studies of antidepressant action in humans and rats have shown that chronic antidepressant drug treatment is accompanied by an attenuation of HPA system activity (Heuser et al 1996;Reul et al 1993Reul et al , 1994. These findings are further supported by the observation that antidepressants lower the levels of CRH in the cerebrospinal fluid of depressed patients (De Bellis et al 1993).…”

mentioning

confidence: 98%