AUTHOR=de Miguel Elena , Vekovischeva Olga , Elsilä Lauri V. , Panhelainen Anne , Kankuri Esko , Aitta-aho Teemu , Korpi Esa R. TITLE=Conditioned Aversion and Neuroplasticity Induced by a Superagonist of Extrasynaptic GABAA Receptors: Correlation With Activation of the Oval BNST Neurons and CRF Mechanisms JOURNAL=Frontiers in Molecular Neuroscience VOLUME=12 YEAR=2019 URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2019.00130 DOI=10.3389/fnmol.2019.00130 ISSN=1662-5099 ABSTRACT=

THIP (gaboxadol), a superagonist of the δ 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 h after administration likely reflecting an anxiety-like state with increased corticosterone release and with central recruitment of corticotropin-releasing factor corticotropin-releasing factor receptor 1 (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 h after administration) and conditioned place aversion by THIP after four daily acute sessions were dependent on extrasynaptic GABAA receptors (abolished in δ-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.