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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2019.00130

Conditioned aversion and neuroplasticity induced by a superagonist of extrasynaptic GABAA receptors: correlation with activation of the oval BNST neurons and CRF mechanisms

Elena de Miguel1, Olga Vekovisceheva1,  Lauri V. Elsilä1,  Anne Panhelainen2,  Esko Kankuri1,  Teemu Aitta-aho1 and  Esa R. Korpi1, 3*
  • 1Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Finland
  • 2Institute of Biotechnology, University of Helsinki, Finland
  • 3University of Helsinki, Finland

THIP (gaboxadol), a superagonist of the delta subunit-containing extrasynaptic GABAA receptors, produces persistent neuroplasticity in dopamine (DA) neurons of the ventral tegmental area (VTA), similarly to rewarding drugs of abuse. However, unlike them THIP lacks abuse potential and induces conditioned place aversion in mice. The mechanism underlying the aversive effects of THIP remains elusive. Here, we show that mild aversive effects of THIP were detected 2 hours after administration likely reflecting an anxiety-like state with increased corticosterone release and with central recruitment of corticotropin-releasing factor CRF1 receptors. A detailed immunohistochemical c-Fos expression mapping for THIP-activated brain areas revealed a correlation between the activation of CRF-expressing neurons in the oval nucleus of the bed nuclei of stria terminalis and THIP-induced aversive effects. In addition, the neuroplasticity of mesolimbic DA system (24 hours after administration) and conditioned place aversion by THIP after 4 daily acute sessions were dependent on extrasynaptic GABAA receptors (abolished in delta-GABAA receptor knockout mice) and activation of the CRF1 receptors (abolished in wildtype mice by a CRF1 receptor antagonist). A selective THIP-induced activation of CRF-expressing neurons in the oval part of the bed nucleus of stria terminalis may constitute a novel mechanism for inducing plasticity in a population of VTA DA neurons and aversive behavioral states.

Keywords: GABA agonist, Anxiety, Aversive Conditioning, glutamate neuroplasticity, VTA dopamine neurons, CRF, BNST

Received: 30 Jan 2019; Accepted: 03 May 2019.

Edited by:

Mary Chebib, University of Sydney, Australia

Reviewed by:

Jamie Maguire, Tufts University School of Medicine, United States
Petra Scholze, Medical University of Vienna, Austria
Petra Van Nieuwenhuijzen, University of Sydney, Australia  

Copyright: © 2019 de Miguel, Vekovisceheva, Elsilä, Panhelainen, Kankuri, Aitta-aho and Korpi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Esa R. Korpi, University of Helsinki, Helsinki, Finland, esa.korpi@helsinki.fi