Selective corticosteroid antagonists modulate specific aspects of spatial orientation learning.

Oitzl, Melly S.; Kloet, E. Ronald de

doi:10.1037/0735-7044.106.1.62

Cited by 561 publications

(414 citation statements)

References 38 publications

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“…The domains of cognitive function that are impaired after blockade of MR in men appear to be remarkably similar to those described in animal studies. In animals, spironolactone impaired interpretation of novel information and processes of evaluation and response selection (Oitzl and de Kloet, 1992;Sandi and Rose, 1994). Furthermore, mutant mice with an inactivated MR gene in the forebrain showed impaired learning and working memory owing to behavioral perseverance and stereotypy (Berger et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…With regard to cognitive function, animal studies have demonstrated that MR are involved in interpretation of novel information (Berger et al, 2006;Oitzl and de Kloet, 1992;Sandi and Rose, 1994), memory retrieval (Conrad et al, 1997;Yau et al, 1995), and visuospatial learning (Douma et al, 1998;Yau et al, 1999;Yau et al, 1995). In healthy humans, only one study examined the interaction of sleep and MR blockade on consolidation of declarative memory and failed to find an effect of MR blockade (Plihal and Born, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Blockade of the Mineralocorticoid Receptor in Healthy Men: Effects on Experimentally Induced Panic Symptoms, Stress Hormones, and Cognition

Otte

Moritz

Yassouridis

et al. 2006

Neuropsychopharmacol

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Animal studies have shown that blockade of central mineralocorticoid receptors (MR) has anxiolytic effects and impairs several aspects of cognitive function. No study to date assessed the effects of MR blockade on anxiety and cognitive function in humans. In the present study, 16 healthy young men were treated either with placebo or with 300 mg spironolactone, a MR-antagonist, at 1100, 1330, and 1630 hours in a balanced cross-over design with the two study conditions being 1 week apart. At 1500 hours, the panic symptoms provoking compound cholecystokinin-tetrapeptide (CCK-4) was administered i.v. on both occasions and panic symptoms were assessed. We measured plasma ACTH and cortisol between 1300 and 1900 hours and assessed cognitive function between 1800 and 1900 hours. CCK-4 elicited panic symptoms and increased ACTH and cortisol secretion in both conditions. Intensity of panic symptoms after CCK-4 was not different between spironolactone and placebo. Spironolactone significantly impaired selective attention and delayed recall of visuospatial memory, and diminished set shifting/mental flexibility on a trend level. Pretreatment with spironolactone led to higher baseline cortisol levels compared to placebo whereas no differences in stimulated cortisol, baseline ACTH, and stimulated ACTH emerged. Blockade of MR with spironolactone increases baseline cortisol secretion and impairs cognitive function but has no effect on experimentally induced panic symptoms in humans, for the study design and dosage of spironolactone used. The domains of cognitive function that are impaired after blockade of MR in men, that is, selective attention, visuospatial memory, and mental flexibility/set shifting appear to be remarkably similar to those described in animal studies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Blockade of the Mineralocorticoid Receptor in Healthy Men: Effects on Experimentally Induced Panic Symptoms, Stress Hormones, and Cognition

Otte

Moritz

Yassouridis

et al. 2006

Neuropsychopharmacol

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“…Comparable stressors which were presented unrelated to a learning paradigm were indeed found to suppress memory Corticosteroid actions in the hippocampus 665 formation (85). Paradoxically, GR activation within the context of a learning situation is essential for consolidation of learned information (86,87). Under such conditions, MR activation was found to mediate behavioural reactivity towards the novel situation (88).…”

Section: Physiologymentioning

confidence: 99%

Corticosteroid Actions in the Hippocampus

Joëls

2001

J Neuroendocrinology

181

111

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Corticosteroid hormones can enter the brain and bind to two intracellular receptor types that regulate transcription of responsive genes: (i) the high af®nity mineralocorticoid receptors and (ii) the glucocorticoid receptors with approximately 10-fold lower af®nity. Although most cells in the brain predominantly express glucocorticoid receptors, principal cells in limbic structures such as the hippocampus often contain glucocorticoid as well as mineralocorticoid receptors. Recent electrophysiological studies have examined the consequences of transcriptional regulation via the two receptor types for information transfer in the hippocampus. It was found that, under resting conditions, corticosteroids do not markedly alter electrical activity. However, if neurones are shifted towards more depolarized or hyperpolarized potentials due to the action of neurotransmitters, slow and adaptive effects of the corticosteroid hormones become apparent. In general, mineralocorticoid receptor occupation maintains steady electrical activity in hippocampal neurones. Brief activation of glucocorticoid receptors leads to increased in¯ux of calcium, which normally helps to slowly reverse temporarily raised electrical activity. These slow and persistent corticosteroid actions will alter network function within the hippocampus, thus contributing to behavioural adaptation in response to stress. Modulation of hippocampal activity by corticosteroids also affects hippocampal output (e.g. to inhibitory interneurones which control hypothalamic-pituitary-adrenal axis activity). The enhanced calcium in¯ux after glucocorticoid receptor activation can become a risk factor when cells are simultaneously exposed to strong depolarizing inputs, such as those occuring during ischaemia. Similarly, chronically elevated corticosteroid levels (or lack of corticosteroids) could endanger hippocampal cell function. The latter may contribute to the precipitation of clinical symptoms in diseases associated with chronically aberrant corticosteroid levels.

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“…This phenomenon could help to explain that in intact rats, spatial learning is exceptionally sensitive to the manipulation of central adrenal steroid receptors (Oitzl, 1998). Thus, for spatial learning, MR activation was related to the strategies adopted during the test, while GR activation was associated with the consolidation of learning (Oitzl and de Kloet, 1992;Oitzl et al, 2001). However, increased and sustained levels of glucocorticoids when administered out of the context of the learning task may interfere with the acquisition or retrieval, thus extinguishing a learned response (Lupien and McEwen, 1997;de Kloet et al, 1999;de Quervain et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Biphasic Effects of Adrenal Steroids on Learned Helplessness Behavior Induced by Inescapable Shock

Kademian

Bignante

Lardone

et al. 2004

Neuropsychopharmacol

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Corticosterone (CS) has been shown to regulate behavior in the learned helplessness (LH) paradigm. Here we provide evidence for a Ushaped relationship between the increasing doses of CS administered and escape failures in the LH model. Replacement with CS (20-400 mg/ml in drinking water) in adrenalectomized (ADX) animals was utilized to examine how the selective activation of mineralocorticoid (MR) and glucocorticoid (GR) receptors is related to the behavioral impairments induced by inescapable shock (IS). Available MR and GR levels were determined in hippocampal cytosol by radioligand binding assays. Non-CS replaced ADX animals showed a high percentage of escape failures assessed 48 h after IS. A CS does of 100 mg/ml given to ADX animals markedly reduced escape failures and resulted in an almost total reduction of available MR associated with a partial reduction of GR. However, the administration of aldosterone (ALDO), a selective MR agonist, was not sufficient to restore normal coping behavior. Moreover, an important role for GR was further shown by means of the specific GR antagonist, RU 38486, which blocked the reduction of LH in ADX rats that were given 100 mg/ml CS. Higher doses of CS given to ADX rats reinstated the LH behavior, and SHAM rats that produced stress CS levels also produced LH behavior. The results indicate a U-shaped dose response function with both negligible and high CS levels being associated with LH behavior. Hence, along with a moderate reduction of available GR level in the cytosol, a large decrease in MR availability seems to be necessary to prevent the acquisition and expression of LH. However, very high reduction of available GR is associated with LH behavior.

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Selective corticosteroid antagonists modulate specific aspects of spatial orientation learning.

Cited by 561 publications

References 38 publications

Blockade of the Mineralocorticoid Receptor in Healthy Men: Effects on Experimentally Induced Panic Symptoms, Stress Hormones, and Cognition

Blockade of the Mineralocorticoid Receptor in Healthy Men: Effects on Experimentally Induced Panic Symptoms, Stress Hormones, and Cognition

Corticosteroid Actions in the Hippocampus

Biphasic Effects of Adrenal Steroids on Learned Helplessness Behavior Induced by Inescapable Shock

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