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Tolerance and antagonism to allopregnanolone effects in the rat CNS
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
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 [en]
Allopregnanolone, GABA-A receptor, UC1011, Spatial memory, Morris Water Maze, Tolerance, Silent second, mRNA
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
URN: urn:nbn:se:umu:diva-804ISBN: 91-7264-073-1 (print)OAI: oai:DiVA.org:umu-804DiVA: diva2:144613
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
List of papers
1. 3beta-20beta-dihydroxy-5alpha-pregnane (UC1011) antagonism of the GABA potentiation and the learning impairment induced in rats by allopregnanolone.
Open this publication in new window or tab >>3beta-20beta-dihydroxy-5alpha-pregnane (UC1011) antagonism of the GABA potentiation and the learning impairment induced in rats by allopregnanolone.
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2004 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 20, no 6, 1604-1612 p.Article in journal (Refereed) Published
Abstract [en]

Allopregnanolone is a progesterone metabolite and GABA-A receptor modulator with benzodiazepine like effects, including decreased learning and memory. In vitro 3beta-hydroxypregnane steroids antagonize allopregnanolone-induced effects, but no antagonism has been shown in vivo. Our purpose was to evaluate 3beta-20beta-dihydroxy-5alpha-pregnane (UC1011) as a blocker of allopregnanolone-induced effects in vivo and in vitro in rats. We tested adult male Wistar rats in the Morris water maze 8 min after daily injections (i.v.) of allopregnanolone 2 mg/kg (n = 21); allopregnanolone : UC1011 2 : 6 (n = 7), 2 : 8 (n = 7), 2 : 20 (n = 14) mg/kg; UC1011 20 mg/kg (n = 14); or vehicle (10% 2-hydroxypropyl-beta-cyclodextrin, n = 4). Studies of chloride ion uptake into cortical and hippocampal membrane preparations were performed. The latency to find the hidden platform was still high in the allopregnanolone-injected group on day 6. Day 3-6 rats injected with allopregnanolone and UC1011 (2 : 20 mg/kg) had lower latency (P < 0.05), compared to the allopregnanolone-injected group. The group that only received UC1011 learned the location of the platform as fast as the controls. There was no significant difference in swim speed between groups. The time spent swimming close to the pool wall was in the allopregnanolone : UC1011 group (2 : 20 mg/kg) significantly decreased (P < 0.05, day 3-6), compared to the allopregnanolone-injected group. The increased chloride ion uptake induced by increasing dosage of allopregnanolone in the presence of 10 micro m GABA was significantly decreased with UC1011 (P < 0.01), in both cortical and hippocampal homogenates. In conclusion, UC1011 can via antagonism at the GABA-A receptor reduce the negative allopregnanolone effect on learning in the water maze.

Keyword
Analysis of Variance, Animals, Behavior; Animal, Cerebral Cortex/drug effects/metabolism, Chlorides/metabolism, Chromatography; High Pressure Liquid/methods, Dose-Response Relationship; Drug, Drug Synergism, GABA Antagonists/*therapeutic use, GABA Modulators/blood/*toxicity, Hippocampus/drug effects/metabolism, Learning Disorders/chemically induced/*drug therapy, Male, Maze Learning/drug effects, Pregnanediol/pharmacology/*therapeutic use, Pregnanolone/blood/pharmacology/therapeutic use/*toxicity, Radioimmunoassay/methods, Rats, Rats; Wistar, Reaction Time/drug effects, Statistics; Nonparametric, Time Factors, gamma-Aminobutyric Acid/physiology
Identifiers
urn:nbn:se:umu:diva-16941 (URN)10.1111/j.1460-9568.2004.03610.x (DOI)15355327 (PubMedID)
Available from: 2007-10-22 Created: 2007-10-22 Last updated: 2017-12-14Bibliographically approved
2. Tolerance development to Morris water maze test impairments induced by acute allopregnanolone
Open this publication in new window or tab >>Tolerance development to Morris water maze test impairments induced by acute allopregnanolone
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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
Keyword
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:nbn:se:umu:diva-22548 (URN)10.1016/j.neuroscience.2005.12.031 (DOI)
Projects
Stress- och könshormoners verkningar på centrala nervsystemet
Available from: 2009-05-13 Created: 2009-05-13 Last updated: 2017-12-13Bibliographically approved
3. GABA(A) receptor changes in acute allopregnanolone tolerance
Open this publication in new window or tab >>GABA(A) receptor changes in acute allopregnanolone tolerance
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2006 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 535, no 1-3, 125-134 p.Article in journal (Refereed) Published
Abstract [en]

To study acute tolerance, rats were anesthetized with interrupted i.v. allopregnanolone infusions where the "silent second" in the electroencephalogram (EEG) was the target. Animals were killed either directly at the first silent second or at the silent second level after 30 or 90 min of anaesthesia. Acute tolerance was demonstrated at 90 min of anaesthesia as earlier shown. In situ hybridization showed a decreased expression of the gamma-aminobutyric acid(A) (GABA(A)) receptor subunit alpha4mRNA amount in the thalamus ventral-posteriomedial nucleus of the tolerant rats. A parallel change in the abundance of the alpha4 subunit was detected with immunohistochemistry. The increase in maintenance dose rate (MDR) was significantly negatively correlated with the alpha4mRNA in the thalamus ventral-posteriomedial nucleus, and positively correlated with alpha2mRNA in different hippocampal subregions. There was also a positive relationship between the alpha1mRNA amounts in the different hippocampal subregions, with significant differences between groups. These changes in GABA(A) receptor subunits mRNA expression and protein (alpha4) might be of importance for the development of acute tolerance to allopregnanolone.

Keyword
Anesthetics/administration & dosage/blood/pharmacokinetics, Animals, Brain/*drug effects/metabolism, Brain Chemistry/drug effects, Dentate Gyrus/chemistry/drug effects/metabolism, Dose-Response Relationship; Drug, Drug Tolerance, Gene Expression/drug effects, Immunohistochemistry, In Situ Hybridization, Infusions; Intravenous, Male, Pregnanolone/*administration & dosage/blood/pharmacokinetics, Protein Subunits/analysis/genetics, RNA; Messenger/genetics/metabolism, Rats, Rats; Sprague-Dawley, Receptors; GABA-A/analysis/*genetics, Receptors; GABA-B/analysis/genetics, Ventral Thalamic Nuclei/chemistry/drug effects/metabolism
Identifiers
urn:nbn:se:umu:diva-16927 (URN)10.1016/j.ejphar.2006.01.059 (DOI)16513107 (PubMedID)
Available from: 2007-12-02 Created: 2007-12-02 Last updated: 2017-12-14Bibliographically approved
4. Persistence of tolerance to the anaesthetic effect of allopregnanolone in male rats
Open this publication in new window or tab >>Persistence of tolerance to the anaesthetic effect of allopregnanolone in male rats
(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-5196 (URN)
Available from: 2006-05-17 Created: 2006-05-17 Last updated: 2011-04-12Bibliographically approved

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