Dissociating anxiolytic and sedative effects of GABA(A)ergic drugs using temperature and locomotor responses to acute stress

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 alpha(1) subunit is associated with sedation, whereas the GABA(A) receptor alpha(2) and alpha(3) subunits are involved in anxiolytic effects. We therefore examined the effects of (non)subunit-selective GABA(A) receptor agonists on temperature and locomotor responses to novel cage stress. Using telemetric monitoring of temperature and locomotor activity, we found that nonsubunit-selective GABA(A) receptor agonist diazepam as well as the alpha(3) subunit-selective receptor agonist TP003 dose-dependently attenuated SIH and locomotor responses. Administration of GABA(A) receptor alpha(1)-selective agonist zolpidem resulted in profound hypothermia and locomotor sedation. The GABA(A) receptor alpha(1)-selective antagonist beta CCt 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 alpha(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. The present study confirms a putative role for the GABA(A) receptor alpha(1) subunit in hypothermia and sedation and supports a role for alpha(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.