umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Persistence of tolerance to the anaesthetic effect of allopregnanolone in male rats
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
(English)Manuscript (Other academic)
Identifiers
URN: urn:nbn:se:umu:diva-5196OAI: oai:DiVA.org:umu-5196DiVA: diva2:144612
Available from: 2006-05-17 Created: 2006-05-17 Last updated: 2011-04-12Bibliographically approved
In thesis
1. Tolerance and antagonism to allopregnanolone effects in the rat CNS
Open this publication in new window or tab >>Tolerance and antagonism to allopregnanolone effects in the rat CNS
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Many studies have suggested a relationship between sex steroids and negative mental and mood changes in women. Allopregnanolone, a potent endogenous ligand of the GABA-A receptor and a metabolite of progesterone, is one of the most accused neuroactive steroids. Variations in the levels of neuroactive steroids that influence the activity of the GABA-A receptor cause a vulnerability to mental and emotional pathology. In women, there are physiological conditions in which allopregnanolone production increases acutely (e.g. stress) or chronically (e.g. menstrual cycle, pregnancy), thus exposing the GABA-A receptor to high allopregnanolone concentrations. In such conditions, tolerance to allopregnanolone probably develops.

We have evaluated the 3β-hydroxy pregnane steroid UC1011 as a functional antagonist to allopregnanolone-induced negative effects in rats. In vivo, we used the Morris Water Maze (MWM) test of learning and, in vitro, we studied chloride ion uptake into cortical and hippocampal membrane preparations. The steroid UC1011 reduces the allopregnanolone-induced learning impairment in the MWM and the increase in chloride ion uptake induced by allopregnanolone. To detect whether chronic tolerance develops to an allopregnanolone-induced condition, male rats were pretreated with allopregnanolone injections for three or seven days. These rats were then tested in the Morris Water Maze for five days and compared with relevant controls. Rats with seven days’ allopregnanolone pretreatment experienced improved performance compared with the acutely allopregnanolone-exposed group, reflecting chronic tolerance development. To study the GABA-A receptor changes in acute allopregnanolone tolerance, we used the silent second (SS) anaesthesia threshold method. At acute tolerance, 90 minutes of anaesthesia, the abundance of the GABA-A receptor α4 subunit and the expression of the α4 subunit mRNA in the thalamus ventral-posteriomedial (VPM) nucleus were reduced. There was also a significant negative correlation between the increase in the allopregnanolone dose needed to maintain anaesthesia and the α4 mRNA in the VPM nucleus. We also investigated whether allopregnanolone tolerance was still present one or two days after the end of the anaesthesia-induced acute tolerance. Tolerance persisted to one day, but not two days, after the treatment and the α4 subunit mRNA expression in the VPM nucleus was negatively related to the allopregnanolone doses needed after one day.

In conclusion, the current thesis shows that the substance UC1011 can reduce the allopregnanolone-induced negative effects in the water maze test. Chronic allopregnanolone tolerance can develop to the effects of allopregnanolone. Allopregnanolone tolerance persists one day after the induction of acute allopregnanolone tolerance. The GABA-A receptor α4 subunit in the thalamus might be involved in the development and persistence of acute tolerance to allopregnanolone.

Place, publisher, year, edition, pages
Umeå: Klinisk vetenskap, 2006. 78 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1026
Keyword
Allopregnanolone, GABA-A receptor, UC1011, Spatial memory, Morris Water Maze, Tolerance, Silent second, mRNA
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-804 (URN)91-7264-073-1 (ISBN)
Public defence
2006-09-15, Betula, 6M, NUS, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2006-05-17 Created: 2006-05-17 Last updated: 2011-08-29Bibliographically approved

Open Access in DiVA

No full text

Search in DiVA

By author/editor
Turkmen, SahruhBackstrom, TorbjornJohansson, Inga-Maj
By organisation
Obstetrics and Gynaecology

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 50 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf