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Positive Allosteric Modulation of α5-GABA(A) Receptors Reverses Stress-Induced Alterations in Dopamine System Function and Prepulse Inhibition of Startle
BACKGROUND: Up to 64% of patients diagnosed with posttraumatic stress disorder (PTSD) experience psychosis, likely attributable to aberrant dopamine neuron activity. We have previously demonstrated that positive allosteric modulators of α5-GABA(A)Rs can selectively decrease hippocampal activity and...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9380714/ https://www.ncbi.nlm.nih.gov/pubmed/35732272 http://dx.doi.org/10.1093/ijnp/pyac035 |
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author | McCoy, Alexandra M Prevot, Thomas D Mian, Md Yenus Cook, James M Frazer, Alan Sibille, Etienne L Carreno, Flavia R Lodge, Daniel J |
author_facet | McCoy, Alexandra M Prevot, Thomas D Mian, Md Yenus Cook, James M Frazer, Alan Sibille, Etienne L Carreno, Flavia R Lodge, Daniel J |
author_sort | McCoy, Alexandra M |
collection | PubMed |
description | BACKGROUND: Up to 64% of patients diagnosed with posttraumatic stress disorder (PTSD) experience psychosis, likely attributable to aberrant dopamine neuron activity. We have previously demonstrated that positive allosteric modulators of α5-GABA(A)Rs can selectively decrease hippocampal activity and reverse psychosis-like physiological and behavioral alterations in a rodent model used to study schizophrenia; however, whether this approach translates to a PTSD model remains to be elucidated. METHODS: We utilized a 2-day inescapable foot shock (IS) procedure to induce stress-related pathophysiology in male Sprague-Dawley rats. We evaluated the effects of intra-ventral hippocampus (vHipp) administration GL-II-73, an α5-GABA(A)R, or viral overexpression of the α5 subunit, using in vivo electrophysiology and behavioral measures in control and IS-treated rats. RESULTS: IS significantly increased ventral tegmental area dopamine neuron population activity, or the number of dopamine neurons firing spontaneously (n = 6; P = .016), consistent with observation in multiple rodent models used to study psychosis. IS also induced deficits in sensorimotor gating, as measured by reduced prepulse inhibition of startle (n = 12; P = .039). Interestingly, intra-vHipp administration of GL-II-73 completely reversed IS-induced increases in dopamine neuron population activity (n = 6; P = .024) and deficits in prepulse inhibition (n = 8; P = .025), whereas viral overexpression of the α5 subunit in the vHipp was not effective. CONCLUSIONS: Our results demonstrate that pharmacological intervention augmenting α5-GABA(A)R function, but not α5 overexpression in itself, can reverse stress-induced deficits related to PTSD in a rodent model, providing a potential site of therapeutic intervention to treat comorbid psychosis in PTSD. |
format | Online Article Text |
id | pubmed-9380714 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-93807142022-08-17 Positive Allosteric Modulation of α5-GABA(A) Receptors Reverses Stress-Induced Alterations in Dopamine System Function and Prepulse Inhibition of Startle McCoy, Alexandra M Prevot, Thomas D Mian, Md Yenus Cook, James M Frazer, Alan Sibille, Etienne L Carreno, Flavia R Lodge, Daniel J Int J Neuropsychopharmacol Regular Research Articles BACKGROUND: Up to 64% of patients diagnosed with posttraumatic stress disorder (PTSD) experience psychosis, likely attributable to aberrant dopamine neuron activity. We have previously demonstrated that positive allosteric modulators of α5-GABA(A)Rs can selectively decrease hippocampal activity and reverse psychosis-like physiological and behavioral alterations in a rodent model used to study schizophrenia; however, whether this approach translates to a PTSD model remains to be elucidated. METHODS: We utilized a 2-day inescapable foot shock (IS) procedure to induce stress-related pathophysiology in male Sprague-Dawley rats. We evaluated the effects of intra-ventral hippocampus (vHipp) administration GL-II-73, an α5-GABA(A)R, or viral overexpression of the α5 subunit, using in vivo electrophysiology and behavioral measures in control and IS-treated rats. RESULTS: IS significantly increased ventral tegmental area dopamine neuron population activity, or the number of dopamine neurons firing spontaneously (n = 6; P = .016), consistent with observation in multiple rodent models used to study psychosis. IS also induced deficits in sensorimotor gating, as measured by reduced prepulse inhibition of startle (n = 12; P = .039). Interestingly, intra-vHipp administration of GL-II-73 completely reversed IS-induced increases in dopamine neuron population activity (n = 6; P = .024) and deficits in prepulse inhibition (n = 8; P = .025), whereas viral overexpression of the α5 subunit in the vHipp was not effective. CONCLUSIONS: Our results demonstrate that pharmacological intervention augmenting α5-GABA(A)R function, but not α5 overexpression in itself, can reverse stress-induced deficits related to PTSD in a rodent model, providing a potential site of therapeutic intervention to treat comorbid psychosis in PTSD. Oxford University Press 2022-06-23 /pmc/articles/PMC9380714/ /pubmed/35732272 http://dx.doi.org/10.1093/ijnp/pyac035 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of CINP. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Regular Research Articles McCoy, Alexandra M Prevot, Thomas D Mian, Md Yenus Cook, James M Frazer, Alan Sibille, Etienne L Carreno, Flavia R Lodge, Daniel J Positive Allosteric Modulation of α5-GABA(A) Receptors Reverses Stress-Induced Alterations in Dopamine System Function and Prepulse Inhibition of Startle |
title | Positive Allosteric Modulation of α5-GABA(A) Receptors Reverses Stress-Induced Alterations in Dopamine System Function and Prepulse Inhibition of Startle |
title_full | Positive Allosteric Modulation of α5-GABA(A) Receptors Reverses Stress-Induced Alterations in Dopamine System Function and Prepulse Inhibition of Startle |
title_fullStr | Positive Allosteric Modulation of α5-GABA(A) Receptors Reverses Stress-Induced Alterations in Dopamine System Function and Prepulse Inhibition of Startle |
title_full_unstemmed | Positive Allosteric Modulation of α5-GABA(A) Receptors Reverses Stress-Induced Alterations in Dopamine System Function and Prepulse Inhibition of Startle |
title_short | Positive Allosteric Modulation of α5-GABA(A) Receptors Reverses Stress-Induced Alterations in Dopamine System Function and Prepulse Inhibition of Startle |
title_sort | positive allosteric modulation of α5-gaba(a) receptors reverses stress-induced alterations in dopamine system function and prepulse inhibition of startle |
topic | Regular Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9380714/ https://www.ncbi.nlm.nih.gov/pubmed/35732272 http://dx.doi.org/10.1093/ijnp/pyac035 |
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