Dissociating anxiolytic and sedative effects of GABAAergic drugs using temperature and locomotor responses to acute stress

Abstract

Rationale The stress-induced hyperthermia (SIH) model is an anxiety model that uses the transient rise in body temperature in response to acute stress. Benzodiazepines produce anxiolytic as well as sedative side effects through nonselective binding to GABA A receptor subunits. The GABA A receptor α 1 subunit is associated with sedation, whereas the GABA A receptor α 2 and α 3 subunits are involved in anxiolytic effects. Objectives We therefore examined the effects of (non) subunit-selective GABA A receptor agonists on temperature and locomotor responses to novel cage stress. Results Using telemetric monitoring of temperature and locomotor activity, we found that nonsubunit-selective GABA A receptor agonist diazepam as well as the α 3 subunit-selective receptor agonist TP003 dose-dependently attenuated SIH and locomotor responses. Administration of GABA A receptor α 1 -selective agonist zolpidem resulted in profound hypothermia and locomotor sedation. The GABA A receptor α 1 -selective antagonist βCCt antagonized the hypothermia, but did not reverse the SIH response attenuation caused by diazepam and zolpidem. These results suggest an important regulating role for the α 1 subunit in thermoregulation and sedation. Ligands of extrasynaptic GABA A receptors such as alcohol and nonbenzodiazepine THIP attenuated the SIH response only at high doses. Conclusions The present study confirms a putative role for the GABA A receptor α 1 subunit in hypothermia and sedation and supports a role for α 2/3 subunit GABA A receptor agonists in anxiety processes. In conclusion, we show that home cage temperature and locomotor responses to novel home cage stress provide an excellent tool to assess both anxiolytic and sedative effects of various (subunit-selective) GABA A ergic compounds.

Distinct Amygdalar AMPAergic/GABAergic Mechanisms Promote Anxiolitic-Like Effects in an Unpredictable Stress Model of the Hamster

“…Interestingly, the modulatory actions of this Gluergic subtype seemed to be influenced by GABAergic inhibitory signals (Gulledge et al 2005) whose functional activities together with the number of synaptic contacts tend to be reduced under chronic stress conditions (Verkuyl et al 2004). For this purpose, it is not surprising that subchronic administration of Zol induces mild anxiolytic effects, since in contrast to some studies handled on animal models (Vinkers et al 2009) and nonhuman primates (Rowlett et al 2005), this selective agonist of α 1 GABA A Rs does not always evoke anxiolytic effects despite promoting such an effect in the EPM test (Carlson et al 2001;Huang et al 2011). Conversely, infusion of CeA with the AMPAergic antagonist alone or in combination (CNQX + Zol) tends to predominantly favor anti-anxiety actions as pointed out by a greater increase in both the percentage of time spent in the open arms together with the number of inputs under subchronic to mild stressful conditions as shown by others (Walker and Davis 2002;da Cunha et al 2008).…”

Kv7 channel modulators reduce the stress-induced hyperthermia response and cause locomotor sedation in rats

“…Also, in our studies, body temperature was already increased before injection stress. This known phenomenon (van Bogaert et al, 2006;Vinkers et al, 2009aVinkers et al, , 2009b may be attributed to early animal disturbance prior to the actual injection stress and the fact that injection of multiple animals takes at least 5 min. In addition, the stress induction method does possess limitations as well.…”

“…Also, at higher doses, severe hypothermia may complicate the interpretation of druginduced effects on the SIH response itself. However, it is important to note that drug-induced effect on the SIH response and general body temperature may be regarded as two independent processes (Vinkers et al, 2009b). This however does not dismiss the notion that at doses that profoundly decrease body temperature, caution should be exerted when interpreting drug-induced effects on the stress-induced increase in body temperature.…”

“…Rats (n¼9-12, total n¼36) received an intraperitoneal injection with vehicle or a drug dose (injection stress) prior to novel cage stress according to the previously published methods (Vinkers et al, 2009b). Injections were given around 10 AM, whereas the novel cage stress procedure occurred 60 min later.…”

“…The stressinduced hyperthermia (SIH) paradigm uses the elevation in body temperature in response to stress mediated by the autonomic nervous system to predict anxiolytic action of pharmacological agents (Vinkers et al, 2008). The resulting robust autonomic SIH response can be selectively reduced with compounds that possess an anxiolytic profile, including (non-)selective benzodiazepines (Vinkers et al, , 2009b. Here, we aimed to use the SIH paradigm to screen for the possible hypothermic and anxiolytic effects of several Kv7 channel modulators in rats using radio telemetry.…”