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Sex and stress steroid modulation of GABA mediated chloride ion flux in rat CNS
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Sex and stress steroids are metabolized to 3a-hydroxy-pregnane-steroid metabolites such as allopregnanolone (Allo) and tetrahydrodeoxycorticosterone (THDOC). Allo and THDOC are neuroactive steroids that are metabolized in the brain and act in brain as potent positive GABAA receptor function modulators. Allo as well as THDOC levels increase during stress. Allo has been associated with a number of symptoms and malfunctions such as impaired memory function and negative mood symptoms in a subgroup of individuals both for animals and humans. Pregnane steroids with 3b-hydroxy-configuration (3b-steroids) have been shown to reduce the Allo enhanced GABA effect.

Aims: The aims for the present thesis were to investigate the effect of 3b-steroids on the GABA mediated GABAA receptor function in presence of positive GABAA receptor modulators. Further, the regional variances between the 3b-steroids as well as the mechanism of the effect were studied. Finally, the effect of stress steroid metabolites on the GABAA receptor function was investigated.

Results: 3b-OH-5a-pregnane-20-one reduced the Allo enhanced GABA mediated chloride ion uptake into cortical microsacs. The 3b-isomer reduced the efficacy of Allo without shift the concentration response curve. It is therefore suggested that the 3b-isomer has a non-competitive effect. Further, it was shown that the 3b-isomer reduced the Allo effect in a selective way since the 3b-isomer did not interact with other positive modulators or with GABA itself. Five tested 3b-steroids reduced the Allo enhanced GABA mediated chloride ion uptake in cerebral cortex and hippocampus as well as the Allo prolongation on spontaneous inhibitory postsynaptic currents (sIPSCs) in preoptic nucleus. In cerebellum on the other hand the 3b-steroids showed to have weaker or no effect compared to the other tested regions. Interestingly, in absence of Allo, two of the 3b-steroids positively modulated the GABA stimulated GABAA receptor function. In absence of Allo, 5b-pregnane-3b,20(R)-diol increased the desensitization rate of current response. In contrast to the reducing effect on the Allo induced prolongation on sIPSCs, the effect of the 3b-steroid on GABA application, was not altered in presence of Allo. The mechanism of the 3b-steroid is therefore suggested being desensitization dependent in contrast to Allo, which has been suggested to decrease the GABA unbinding rate. In contrast to the enhanced effect of Allo, glucocorticoid metabolites reduced the GABA mediated chloride ion uptake in a concentration dependent way. The results in present thesis indicate that both sex and stress steroid metabolites interact with the GABAA receptor function. The knowledge that diversity of endogenous steroids interact with the GABAA receptor function is of importance for further understanding of different sex and stress steroid related symptoms and syndromes.

Place, publisher, year, edition, pages
Umeå: Klinisk vetenskap , 2007. , 64 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1091
Keyword [en]
allopregnanolone, chloride ion uptake, patch-clamp, 3beta-steroids, kinetic parameters, rat brain
National Category
Clinical Science
Identifiers
URN: urn:nbn:se:umu:diva-1056ISBN: 978-91-7264-269-0 (print)OAI: oai:DiVA.org:umu-1056DiVA: diva2:140064
Public defence
2007-04-13, Hörsal Betula, 6M, bv, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2007-03-27 Created: 2007-03-27 Last updated: 2011-04-07Bibliographically approved
List of papers
1. Allopregnanolone-stimulated GABA-mediated chloride ion flux is inhibited by 3beta-hydroxy-5alpha-pregnane-20-one (isoallopregnanolone)
Open this publication in new window or tab >>Allopregnanolone-stimulated GABA-mediated chloride ion flux is inhibited by 3beta-hydroxy-5alpha-pregnane-20-one (isoallopregnanolone)
2003 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 982, no 1, 45-53 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-2183 (URN)10.1016/S0006-8993(03)02939-1 (DOI)12915239 (PubMedID)
Available from: 2007-03-27 Created: 2007-03-27 Last updated: 2015-11-11Bibliographically approved
2. Neurosteroid modulation of allopregnanolone and GABA effect on the GABA-A receptor
Open this publication in new window or tab >>Neurosteroid modulation of allopregnanolone and GABA effect on the GABA-A receptor
Show others...
2006 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 143, no 1, 73-81 p.Article in journal (Refereed) Published
Keyword
Analysis of Variance, Animals, Brain/cytology, Cells; Cultured, Chloride Channels/drug effects/physiology, Chlorides/metabolism, Dose-Response Relationship; Drug, Drug Interactions, Male, Membrane Potentials/drug effects/physiology/radiation effects, Neurons/*drug effects/physiology, Patch-Clamp Techniques/methods, Pregnanolone/*pharmacology, Rats, Rats; Wistar, Receptors; GABA-A/*metabolism, Steroids/*pharmacology, gamma-Aminobutyric Acid/*pharmacology
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-10000 (URN)10.1016/j.neuroscience.2006.07.031 (DOI)16938407 (PubMedID)
Available from: 2008-06-04 Created: 2008-06-04 Last updated: 2012-10-10Bibliographically approved
3. The neuroactive steroid 5beta-pregnane-3beta, 20(R)-diol alters the kinetic properties of the GABA-A receptor differently from pregnenolone-sulfate
Open this publication in new window or tab >>The neuroactive steroid 5beta-pregnane-3beta, 20(R)-diol alters the kinetic properties of the GABA-A receptor differently from pregnenolone-sulfate
Show others...
(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-2185 (URN)
Available from: 2007-03-27 Created: 2007-03-27 Last updated: 2015-11-11Bibliographically approved
4. Rapid non-genomic effect of glucocorticoid metabolites and neurosteroids on the gamma-aminobutyric acid-A receptor
Open this publication in new window or tab >>Rapid non-genomic effect of glucocorticoid metabolites and neurosteroids on the gamma-aminobutyric acid-A receptor
2005 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 21, no 8, 2083-2088 p.Article in journal (Other academic) Published
Keyword
Animals, Cerebral Cortex/*cytology, Chlorides/metabolism, Desoxycorticosterone/*analogs & derivatives/pharmacology, Dose-Response Relationship; Drug, Drug Interactions, Glucocorticoids/*metabolism/*pharmacology, Male, Neurons/*cytology/drug effects/metabolism, Pregnanolone/pharmacology, Rats, Rats; Wistar, Receptors; GABA-A/*metabolism, Synaptosomes/*drug effects, gamma-Aminobutyric Acid/pharmacology
Identifiers
urn:nbn:se:umu:diva-9999 (URN)10.1111/j.1460-9568.2005.04047.x (DOI)15869504 (PubMedID)
Available from: 2008-06-04 Created: 2008-06-04 Last updated: 2012-10-10Bibliographically approved

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