Elucidating GABAB and GABAB Receptor Functions in Anxiety Using the Stress-Induced Hyperthermia Paradigm: A Review

Abstract

Exposure to acute psychological or physical stress increases core body temperature (stress-induced hyperthermia, SIH) which is part of the autonomic stress response. SIH is used as a putative rodent anxiety paradigm in which anxiolytic drugs reduce the SIH response. The predictive validity of the SIH paradigm has proven to be good, making it suitable to detect the putative anxiolytic properties of drugs. So far, GABA receptor agonists including benzodiazepines and hypnotics have proven to attenuate the SIH response. The GABAA receptor has been known to be closely involved in the acute stress response. Also, the recent development of compounds with selective efficacy for different subunits at the benzodiazepine site of the GABAA receptor has renewed interest for the therapeutic potential of GAB ergic drugs. Moreover, metabotropic (GABAB) receptor agonists reduce the SIH response. GABAB receptors are ubiquitously expressed in the central nervous system, and there is evidence for a role of the GABAB receptor in anxiety. Thus, both drugs acting on the GABAA and the GABAB receptor are generally able to attenuate the SIH response, and this review presents a detailed overview of the effects of both drug classes on the SIH response. As the GABA receptor family is diverse and complex, this paradigm may contribute to the elucidation of the putative effects of GABA ergic drugs in emotional disorders such as anxiety and depression

Lifelong CRF overproduction is associated with altered gene expression and sensitivity of discrete GABAA and mGlu receptor subtypes

“…Our results confirm and extend the SIH-reducing effects of (non-)selective GABAergic modulators diazepam, zolpidem, and TP003 (for review, see (Vinkers et al 2010b )) as well as those of the glutamatergic compounds (mGluR 2/3 agonists and mGluR 5 antagonists) (Nordquist et al 2007 ; Spooren et al 2002 ). The fact that the α 5 -subunit preferential GABA A receptor agonist SH-053-2′F-R-CH 3 did not affect basal body temperature nor the SIH response compared to vehicle-treated mice may suggest that the α 5 subunit is not involved in the anxiolytic and hypothermic effects of benzodiazepines, which is in line with the already published findings (Atack 2011 ; Rudolph and Mohler 2006 ; Savic et al 2010 ).…”

GABAA Receptor α Subunits Differentially Contribute to Diazepam Tolerance after Chronic Treatment

“…However, a role for GABA A -α 2 /α 3 receptors in mediating hypothermic tolerance to acute diazepam challenge cannot be fully excluded since zolpidem is only 10–15 fold affinity selective for GABA A -α 1 over GABA A -α 2 /α 3 receptors [1] , and at the dose used here this might be sufficient to activate these receptor subtypes in-vivo. Also, we cannot fully exclude the possibility that the presence of alcohol in pumps may have potentially confounded our data, even though the amounts are well marginal compared to the acute doses of 2–4 g/kg that are needed to affect body temperature [34] .…”

Avances en enfoques multidisciplinarios y en diversas especies para el examen de la neurobiología de los trastornos psiquiátricos

“…En el ser humano existen evidencias que indican que las respuestas de estrés del sistema autónomo están correlacionadas con los niveles de estrés percibidos, modulados probablemente por procesos que tienen lugar en las amígdalas cerebrales (Carrasco y Van de Kar, 2003). Los mecanismos GABAA-érgicos y serotoninérgicos cerebrales desempeñan un papel importante en la modulación de la HIE (Vinkers et al, 2010a(Vinkers et al, , 2010b, y los estudios humanos y de roedores sobre los mecanismos cerebrales subyacentes indican una elevada comparabilidad translacional (Ulrich-Lai y Herman, 2009). Esto hace que el paradigma de la HIE constituya un paradigma translacional atractivo.…”