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
Tolerance development to Morris water maze test impairments induced by acute allopregnanolone
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. (UNC, Torbjörn Bäckström)
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. (UNC, Torbjörn Bäckström)
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. (UNC, Torbjörn Bäckström)
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. (UNC)
Show others and affiliations
2006 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 139, no 2, 651-659 p.Article in journal (Refereed) Published
Abstract [en]

The progesterone metabolite allopregnanolone, like benzodiazepines, reduces learning and impairs memory in rats. Both substances act as GABA agonists at the GABA-A receptor and impair the performance in the Morris water maze test. Women are during the menstrual cycle, pregnancy, and during hormone replacement therapy exposed to allopregnanolone or allopregnanolone-like substances for extended periods. Long-term benzodiazepine treatment can cause tolerance against benzodiazepine-induced learning impairments. In this study we evaluated whether a corresponding allopregnanolone tolerance develops in rats. Adult male Wistar rats were pretreated for 3 days with i.v. allopregnanolone injections (2 mg/kg) one or two times a day, or for 7 days with allopregnanolone injections 20 mg/kg intraperitoneally, twice a day. Thereafter the rats were tested in the Morris water maze for 5 days and compared with relevant controls. Rats pretreated with allopregnanolone twice a day had decreased escape latency, path length and thigmotaxis compared with the acute allopregnanolone group that was pretreated with vehicle. Pretreatment for 7 days resulted in learning of the platform position. However, the memory of the platform position was in these tolerant rats not as strong as in controls only given vehicle. Allopregnanolone treatment was therefore seen to induce a partial tolerance against acute allopregnanolone effects in the Morris water maze.

Place, publisher, year, edition, pages
Elsevier Inc. , 2006. Vol. 139, no 2, 651-659 p.
Keyword [en]
Rat, animal, tolerance, withdrawal, allopregnanolone, morris water maze, learning, memory
National Category
Pharmacology and Toxicology Endocrinology and Diabetes Clinical Science Medical and Health Sciences
Research subject
Obstetrics and Gynaecology
Identifiers
URN: urn:nbn:se:umu:diva-22548DOI: 10.1016/j.neuroscience.2005.12.031OAI: oai:DiVA.org:umu-22548DiVA: diva2:217071
Projects
Stress- och könshormoners verkningar på centrala nervsystemet
Available from: 2009-05-13 Created: 2009-05-13 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
2. Behavioral effects of female sex steroid hormones : models of PMS and PMDD in Wistar rats
Open this publication in new window or tab >>Behavioral effects of female sex steroid hormones : models of PMS and PMDD in Wistar rats
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background Animal models can be used to mimic human conditions of psychopathology, and also as pre-clinical models to evaluate candidate drugs. With hormonal treatment it is possible to produce behavior in the rat which corresponds to the mental symptoms of pre-menstrual syndrome (PMS), and pre-menstrual dysphoric disorder (PMDD). PMS affects 25-30 % of all women in fertile age and 3-8% are diagnosed with the more severe condition PMDD. The cardinal mental symptoms are; irritability, mood-swings, depression, anxiety, fatigue, insomnia, difficulties with concentration and memory and learning difficulties. The symptoms of PMS/PMDD occur in the luteal phase in conjunction with increasing concentrations of progesterone (P4) and P4-metabolites. In anovulatory cycles the symptoms are absent. The hormones which produce the monthly reoccurring negative symptoms on mood are foremost the neuroactive metabolites; allopregnanolone (ALLO) and tetrahydro-deoxycorticosterone (THDOC). ALLO is produced by the corpus luteum, but can also be synthesized in the brain, both ALLO and THDOC can also be released from the adrenal cortex during stress. These steroids are active on the inhibitory GABA neurotransmitter system through the GABAA receptor, and the effects are similar to that of alcohol and benzodiazepines. These steroids have strong sedative and hypnotic effects. A paradox is that some individuals seem to react with negative mood on sex steroids while all fertile women have the cyclical steroid changes during the menstrual cycle. Some individuals are more sensitive to neuroactive steroids with influences of personality, heritability and stress factors.

Aims The thesis aims were to develop pre-clinical animal models of PMS/PMDD and to investigate induction of ALLO tolerance, individual sensitivity to neurosteroids and the interactions between chronic social stress and neurosteroids.

Methods In these studies male and female Wistar rats were used to test steroid hormone effects on learning and memory and behaviors analogous to negative mood symptoms. This was accomplished through hormonal treatment and a subsequent withdrawal period from P4 (P4) + estradiol (E2) (PEWD), or ALLO. To assess tolerance, memory and learning in the Morris water maze (MWM) was studied. Anxiety-like behaviors were tested with the elevated plus maze (EPM), open field test (OFT), and the intruder test (IT). The EPM or OFT was used to classify the rats as high or low responders on risk-taking and explorative behavior (HR/LR). For social ranking order assessment the tube test (TT) and food competition test (FCT) were used. Chronic social stress was accomplished through co-habituation with two older rats (chronic subordination stress). In female rats the estrous cycle followed using staining of vaginal smears. Concentration of corticosterone (CORT) was measured by radio-immuno-assay (RIA).

Results In the MWM ALLO pre-treatment produced tolerance to the acute negative ALLO effects. Both male and female rats showed behavioral correlations between the EPM and OFT tests, and correlations were also seen in CORT levels. Individuals with the stable trait of high risk-taking and explorative behavior (HR) were more sensitive to PEWD induction of anxiety-like behavior. These animals also showed decreased CORT levels during withdrawal. Chronic subordination stress enhanced the response to PEWD on measures of locomotor activity and social anxiety-like behavior.

Conclusions It is possible to induce tolerance to the negative ALLO effects on learning and memory. The animal models of anxiety-like behavior show an individual PEWD response profile where HR rats are more sensitive. Exposure to chronic social stress enhanced the PEWD response. Hence there are both inherent and environmental factors behind the behavioral response to steroid hormones in rats.

Place, publisher, year, edition, pages
Umaå: Department of Clinical Sciences, Division of Obstetrics and Gynecology, 2009. 90 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1268
Keyword
PMS, PMDD, rats, progesterone, estradiol, behavior, individual response, stress interaction, tolerance, withdrawal, learning and memory, anxiety.
National Category
Pharmacology and Toxicology Endocrinology and Diabetes Obstetrics, Gynecology and Reproductive Medicine Pharmacology and Toxicology Clinical Science Psychology
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-22557 (URN)978-91-7264-796-1 (ISBN)
Distributor:
Obstetrik och gynekologi, 901 87, Umeå
Public defence
2009-06-12, Betula, byggnad 6M, NUS, NUS 901 85, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Projects
Stress- och könshormoners verkningar på centrala nervsystemet
Available from: 2009-05-19 Created: 2009-05-13 Last updated: 2010-01-18Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textNeuroscience

Authority records BETA

Türkmen, SahruhLöfgren, MagnusBäckström, TorbjörnJohansson, Inga-Maj

Search in DiVA

By author/editor
Türkmen, SahruhLöfgren, MagnusBäckström, TorbjörnJohansson, Inga-Maj
By organisation
Obstetrics and Gynaecology
In the same journal
Neuroscience
Pharmacology and ToxicologyEndocrinology and DiabetesClinical ScienceMedical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 229 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