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Chronic subordination stress augments combined progesterone and estradiol withdrawal behavior
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. (Torbjörn Bäckström, UNC)
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. (Torbjörn Bäckström, UNC)
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. (Torbjörn Bäckström, UNC)
Department of Neuroscience, Division of Pharmacology, Box 593, BMC, SE-751 24 Uppsala, Sweden..
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(English)Manuscript (Other academic)
Abstract [en]

Exposure to stress is a risk factor for developing pre-menstrual syndrome (PMS) and pre-menstrual dysphoric disorder (PMDD), and stress enhances the anxiogenic effect of female sex steroids in animals. This study examines the interaction between chronic subordination stress and withdrawal from progesterone (P4) and estradiol (E2) (PEWD) in producing behaviors analogous to anxiety and irritability in rats. At the start of the experiment, male Wistar rats were housed in triads consisting of one younger rat (~35 days) and two older rats (~50 days). The housing condition was aimed at producing chronic subordination stress in the younger animals. Chronic subordination stress was assessed by the elevated plus maze (EPM) and by corticosterone (CORT) analysis. A triad of three 35-day-old rats was used as age control. Social rank within the triads was determined using a food competition test (FCT) and the tube test (TT). The younger rats (subordinate) and the dominant rats were assigned to 10 days of treatment with 5 mg/kg progesterone combined with 10 µg/kg 17β estradiol. Twenty-four hours after the last injection, the subordinate and dominant animals were tested in the open-field test (OFT) and in the intruder test (IT). The IT consists of a 10-minute exposure to 3 unfamiliar rats. Chronic subordination stress reduced EPM open-arm time and altered the CORT response. It also made the subordinate animals more vulnerable to PEWD. The effects were increased locomotion in the OFT, increased defensive burying, and increased social anxiety in the intruder test (IT). Dominant animals did not react to PEWD. Thus, chronic subordination stress augments PEWD.

National Category
Endocrinology and Diabetes Pharmacology and Toxicology Pathobiology Clinical Science
Research subject
Obstetrics and Gynaecology
Identifiers
URN: urn:nbn:se:umu:diva-22545OAI: oai:DiVA.org:umu-22545DiVA: diva2:217064
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. 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

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