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Progesterone withdrawal effects in the open field test can be predicted by elevated plus maze performance
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.
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2006 (English)In: Hormones and Behavior, ISSN 0018-506X, E-ISSN 1095-6867, Vol. 50, no 2, 208-215 p.Article in journal (Refereed) Published
Abstract [en]

Allopregnanolone (3alpha-hydroxy-5alpha-pregnane-20-one) is a ring-A-reduced metabolite of progesterone, which is naturally produced during the luteal phase of the menstrual cycle, during pregnancy and by stressful events. The steroid hormone inhibits neural functions through increased chloride ion flux through the GABAA receptor. The effects and subsequent withdrawal symptoms are similar to those caused by alcohol, benzodiazepines and barbiturates. This study examined the withdrawal effects of progesterone with regards to the influence of individual baseline exploration and risk taking. Rats were tested on the elevated plus maze (EPM) before hormonal treatment, in order to evaluate differences in risk taking and exploration of open and elevated areas. Treatment consisted of ten consecutive once a day progesterone or vehicle s.c. injections. On the last day of treatment, estradiol was injected in addition to progesterone, followed by a 24-h withdrawal before testing in the open field test (OF). Progesterone-treated rats showed a withdrawal effect of open area avoidance in the OF. The vehicle-treated control rats showed strong correlations between the EPM and OF parameters. This relationship was not found for the progesterone group at withdrawal. Rats with greater numbers of open arm entrance in the EPM pretest showed an increased sensitivity to progesterone withdrawal (PWD) compared to rats with low exploration and risk taking. The results indicate that the effects of PWD relate to individual exploration and risk taking. Furthermore, the possible analogy of PWD and PMS/PMDD in relation to individual traits is discussed.

Place, publisher, year, edition, pages
2006. Vol. 50, no 2, 208-215 p.
Keyword [en]
Animals, Anxiety/*psychology, Behavior; Animal/drug effects/*physiology, Exploratory Behavior/physiology, Male, Motor Activity/physiology, Progesterone/*adverse effects, Rats, Rats; Wistar, Receptors; GABA-A/drug effects, Risk-Taking, Substance Withdrawal Syndrome/*psychology
URN: urn:nbn:se:umu:diva-16926DOI: 10.1016/j.yhbeh.2006.03.002PubMedID: 16677649OAI: diva2:156599
Available from: 2007-10-22 Created: 2007-10-22 Last updated: 2011-04-12Bibliographically approved
In thesis
1. 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.
Umeå University medical dissertations, ISSN 0346-6612 ; 1268
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
urn:nbn:se:umu:diva-22557 (URN)978-91-7264-796-1 (ISBN)
Obstetrik och gynekologi, 901 87, Umeå
Public defence
2009-06-12, Betula, byggnad 6M, NUS, NUS 901 85, Umeå, 09:00 (Swedish)
Stress- och könshormoners verkningar på centrala nervsystemet
Available from: 2009-05-19 Created: 2009-05-13 Last updated: 2010-01-18Bibliographically approved

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Löfgren, MagnusJohansson, Inga-MajLundgren, PerBäckström, Torbjörn
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