Penzinger, Reka;
(2024)
Role of neurosteroid modulation of GABAA receptors in the central actions of alcohol.
Doctoral thesis (Ph.D), UCL (University College London).
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Reka Penzinger PhD Thesis - Revised.pdf - Accepted Version Access restricted to UCL open access staff until 1 December 2025. Download (9MB) |
Abstract
Inhibitory GABA-mediated neurotransmission is considered to be vitally important for mediating the major effects of alcohol in the brain. Recent studies have suggested that certain behavioural and electrophysiological actions of ethanol are dependent on increased concentrations of brain-derived neuroactive steroids. These neurosteroids, such as allopregnanolone and tetrahydro-deoxycorticosterone, are potent endogenous positive modulators of GABA type-A receptors (GABAARs), and are synthesised de novo in the brain, or from the peripherally-derived hormones, progesterone and corticosterone. To investigate the role of neurosteroid modulation of specific isoforms of GABAA receptors in alcohol-driven reward behaviour, we have assessed ethanol consumption in two novel knock-in mouse models, α2Q241M and α4Q246M, which removes neurosteroid potentiation from α2-GABAA and α4-containing GABAA receptors, respectively. This study shows that both α2- and α4- neurosteroid insensitive mice exhibit reduced ethanol intake when assessed by an intermittent access two-bottle choice protocol. By contrast, saccharin and quinine solution intakes remained unchanged. The importance of neurosteroid levels was further demonstrated by using finasteride, a neurosteroid synthesis inhibitor. This reduced the preference for ethanol intake in C57BL/J6, α2Q241M and α4Q246M mice, as well as reducing blood ethanol concentrations. To explore whether altered modulation of inhibitory synaptic transmission might underpin these behavioural phenotypes, whole-cell electrophysiological recordings were performed from dentate gyrus granule cells (DGGCs) during application of ethanol. Upon acute exposure to ethanol, increased miniature inhibitory post-synaptic current amplitude, frequency, decay kinetics and charge transfer were observed. However, no overall differences were detected between wild type and α2 and α4 mutant expressing neurons, indicating that these changes are not mediated via neurosteroid modulation of α2- and α4-GABAARs at least in DGGCs. In conclusion, this study demonstrates that neurosteroids are playing an important role in mediating the central actions of ethanol via α2- and α4-GABAARs but such GABAA receptors in DGGCs are not majorly involved in these effects of the neurosteroids.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Role of neurosteroid modulation of GABAA receptors in the central actions of alcohol |
| Language: | English |
| Additional information: | Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10200033 |
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