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Dissertation
Steroid hormone withdrawal alters the GABA-A receptor pharmacological profile: an electrophysiological study
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Dec 1999
DOI:
https://doi.org/10.17918/00009366
Abstract
The steroid hormone progesterone (P) is readily converted to 3[alpha]-OH-5[alpha]-pregnan-20-one (3[alpha], 5[alpha]-THP) in the brains of males and females. 3[alpha], 5[alpha]-THP, like benzodiazepines (BDZs), can mediate sedative effects to decrease anxiety and seizure susceptibility by potentiating the function of GABA, the major inhibitory neurotransmitter in the brain. Clinical symptoms of pre-menstrual syndrome (PMS) such as anxiety is strongly correlated with abrupt declines in circulating levels of P as well as its GABA-modulatory metabolite, 3[alpha], 5[alpha]-THP. However, we understand little of the changes in GABAA receptor (GABA-R) pharmacology after P withdrawal. One goal of this research was to characterize GABA-mediated function after P withdrawal using electrophysiological means. Towards this end, a multiple P-withdrawal paradigm was designed to mimic PMS and post-partum syndrome in a rat model. The hypothesis tested electrophysiologically was that withdrawal from elevated circulating levels of the female sex steroid P may change electrophysiological parameters of the GABA-R. Twenty-four hours after removal of a three-week s.c. P capsule implant (24 hours P withdrawal), the pharmacological profile of GABA-R was changed; there was a 70-100% reduction in the ability of lorazepam (LZM), a BDZ agonist, to potentiate GABA-evoked Cl- current in acutely isolated hippocampal CA1 neurons. This effect was a result of withdrawal from 3[alpha], 5[alpha]-THP rather than P, as blockade of 3[alpha], 5[alpha]-THP formation with indomethacin during chronic P treatment prevented the BDZ insensitivity. To test the hypothesis that decreases in total integrated GABA-gated current observed in the isolated CA1 pyramidal cells would be manifested as reduced GABA inhibition at the circuit level, the paired-pulse inhibition (PPI) paradigm was used to evaluate the GABA-R-mediated effects in hippocampal slices. In order to test the hypothesis that [alpha]4-subunit up-regulation may produce the observed changes in GABA-R pharmacology, antisense oligonucleotide administration was used to suppress expression of the [alpha]4 subunit of GABA-R induced by P withdrawal. The results indicate that treatment prevented most withdrawal effects such as LZM insensitivity, the altered pharmacological profile, the decreased PPI, and the decreased GABA current decay time constant in isolated neurons. (Abstract shortened by UMI.).
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Details
- Title
- Steroid hormone withdrawal alters the GABA-A receptor pharmacological profile
- Creators
- Fu-Chun Robert Hsu
- Contributors
- Sheryl S. Smith (Advisor) - Drexel University, Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Awarding Institution
- Medical College of Pennsylvania and Hahnemann University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Medical College of Pennsylvania and Hahnemann University; Philadelphia, Pennsylvania
- Number of pages
- xi, 145 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021888717504721