Specificity of the Adrenal Steroid Receptor System in Rat Hippocampus*

Veldhuis, H D; Koppen, C. van; Ittersum, Marjanne Van; Kloet, E. R. de

doi:10.1210/endo-110-6-2044

Cited by 217 publications

(93 citation statements)

References 21 publications

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“…Using comparable monolayers to those in this study, Ueda et al (1992) have demonstrated that aldosterone is moderately transported by the human MDR1 Pgp, while Bourgeois et al (1993) showed that cortexolone was not and aldosterone was only weakly transported by mdr1b Pgp. The weak transport of aldosterone by Pgp cannot explain why this mineralocorticoid seems to play a limited role in limbic functioning relative to corticosterone, while both steroids bind with similar affinity to MR in vitro (Veldhuis et al 1982, De Kloet 1991. Moreover, upon administration of tracer amounts of ]aldosterone to adrenalectomised rodents both steroids are retained very well in limbic brain structures that abundantly express MR (Birmingham et al 1984).…”

Section: Discussionmentioning

confidence: 98%

The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone

Karssen¹,

Meijer²,

Sandt³

et al. 2002

Journal of Endocrinology

102

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In the present study, we have investigated the role of the multidrug resistance (mdr) P-glycoprotein (Pgp) at the blood-brain barrier in hampering the access of the synthetic glucocorticoid, prednisolone.In vivo, a tracer dose of [ 3 H]prednisolone poorly penetrated the brain of adrenalectomised wild-type mice, but the uptake was more than threefold enhanced in the absence of Pgp expression in mdr1a ( / ) mice. In vitro, in stably transfected LLC-PK1 monolayers the human MDR1 P-glycoprotein was able to transport prednisolone present at a micromolar concentration. A specific Pgp blocker, LY 335979, could block this polar transport of The ability of Pgp to export the synthetic glucocorticoid, prednisolone, suggests that uptake of prednisolone in the human brain is impaired, leading to a discrepancy between central and peripheral actions. Furthermore, the ensuing imbalance in activation of the two types of brain corticosteroid receptors may have consequences for cognitive performance and mood.

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Section: Discussionmentioning

confidence: 98%

The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone

Karssen¹,

Meijer²,

Sandt³

et al. 2002

Journal of Endocrinology

102

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“…High endogenous baseline levels or exogenous administration of glucocorticoids or stress prior to the study phase of a memory task is associated with better performance under some circumstances (Abercrombie et al, 2003;Akirav et al, 2004;Beckwith, Petros, Scaglione, & Nelson, 1986;Bemelmans, Goekoop, De Rijk, & Van Kempen, 2002;Domes, Heinrichs, Reichwald, & Hautzinger, 2002;Fehm-Wolfsdorf, Reutter, Zenz, Born, & Fehm, 1993;Lupien, Wilkinson, Brière, Mènard, et al, 2002;Putman, van Honk, Kessels, Mulder, & Koppeschaar, 2004;Shors, Weiss, & Thompson, 1992;Wilson, Wilson, & Dicara, 1975), but not under others (Kirschbaum, Wolf, May, Wippich, & Hellhammer, 1996;Lupien, Gillin, & Hauger, 1999;Maheau et al, 2004;Wolf, Convit, et al, 2001;Wolf, Schommer, Hellhammer, McEwen, & Kirschbaum, 2001;Wolkowitz et al, 1990). Such differences across studies are likely due to complex interactions between such factors as the proposed inverted U-shaped dose response function of glucocorticoids (Conrad, Lupien, & McEwen, 1999;Diamond, Bennett, Fleshner, & Rose, 1992;Kovacs, Telegdy, & Lissak, 1977;, putatively distinctive roles of different receptor types (de Kloet, 2004;Oitzl & de Kloet, 1992;Veldhuis, Van Koppen, Van Ittersum, & de Kloet, 1982), and the natural diurnal variation in glucocorticoid levels (Fehm-Wolfsdorf et al, 1993;Lupien et al, 1999;Lupien, Wilkinson, Brière, Mènard, et al, 2002). It is also important to consider that it is difficult to dissociate the effects on memory acquisition from the impairing effects on memory retrieval (de Quervain et al, 1998;de Quervain et al, 2000), since some experimental manipulations may affect both phas...…”

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confidence: 99%

Sex, stress, and fear: Individual differences in conditioned learning

Zorawski

Cook

Kuhn

et al. 2005

Cognitive, Affective, & Behavioral Neuroscience

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“…The choice of hippocampal corticosterone receptors as a measure for a possible trophic effect of ORG 2766 was based on the following considerations. The corticosterone receptor system has its predominant localization in the hippocampal neurons 13,17,23,24,42,43. In rats the action of corticosterone on extinction of certain learned responses4,23, 26 and on exploration of a novel environment40, at displays the same stringent specificity as the corticosterone binding to the hippocampal corticosterone receptor system 42.…”

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confidence: 99%

Spatial learning and the hippocampal corticosterone receptor system of old rats: effect of the ACTH4–9 analogue ORG 2766

Rigter¹,

Veldhuis

Kloet

1984

Brain Research

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Key words: corticosterone receptors --ACTH4_ 9 analogue --hippocampus --spatial learning --aging Old (26 months) and young (6 months) male Wistar rats were treated chronically for 2 weeks with ORG 2766 or with vehicle, delivered via subcutaneously implanted minipumps (0.5/~g peptide/0.5/~l/h). Learning of a spatial task was not impaired in the old animals, except for one measure, i.e. the latency to find the goal box. In neither age group did ORG 2766 influence behavioral performance. The number of corticosterone receptor sites was decreased in the hippocampus of senescent rats, but restored to the level observed in young rats following ORG 2766 treatment. It is concluded that the number of hippocampal corticosterone receptor sites is a sensitive index of brain aging and effectiveness of ORG 2766.ORG 2766 (H-Met(O2)-Glu-His-Phe-D-Lys-Phe-OH) is a behaviorally active ACTH4_ 9 analogue. The peptide increases responsiveness of rats to motivationally relevant stimuli14.20, 31, speeds regeneration of injured peripheral nervesS and enhances mood, when given chronically to elderly persons 31. In rats age-associated changes in hippocampus morphology can be influenced by chronic treatment with ORG 2766. The ACTH4_ 9 analogue delayed the development of astrocyte hypertrophy in the hippocampus of aging rats21,22The hippocampus is involved in spatial orientation 30. Senescent rats have been found to display a deficit in learning the lay-out of a circular platform2,37. Chronic treatment with ORG 2766 restored performance of old female rats to the level of young control animals 37.Thus, the effect of chronic treatment with ORG 2766 is expressed in changes in brain morphology, learning, mood and nerve regeneration. We assume that some, if not all of these expressions of the activity of the peptide have a common denominator, e.g. some trophic effect on neural tissue, which may slow down the process of brain aging. It is of great importance to localize and characterize such an effect of ACTH-related peptides in the brain and to find sensitive indices for its operation.In this study we examined the susceptibility of spatial learning and of hippocampal corticosterone receptors to aging and to ORG 2766 treatment. As a follow-up of a previous study 37, we used male rats of the same strain. The choice of hippocampal corticosterone receptors as a measure for a possible trophic effect of ORG 2766 was based on the following considerations. The corticosterone receptor system has its predominant localization in the hippocampal neurons 13,17,23,24,42,43. In rats the action of corticosterone on extinction of certain learned responses4,23, 26 and on exploration of a novel environment40, at displays the same stringent specificity as the corticosterone binding to the hippocampal corticosterone receptor system 42. Moreover, an age-associated decline in receptor capacity for glucocorticoids has been reported in neurons of rat forebrain 34 and of hippocampus 35. Recent studies have shown, that vasopressin-and ACTH-related peptides are involved in...

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Specificity of the Adrenal Steroid Receptor System in Rat Hippocampus*

Cited by 217 publications

References 21 publications

The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone

The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone

Sex, stress, and fear: Individual differences in conditioned learning

Spatial learning and the hippocampal corticosterone receptor system of old rats: effect of the ACTH4–9 analogue ORG 2766

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