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


OBJECTIVE
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 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 betaCCt 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.


CONCLUSIONS
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.
Vinkers
Christiaan H
CH
Department of Psychopharmacology, Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands. c.h.vinkers@uu.nl
Klanker
Marianne
M
Groenink
Lucianne
L
Korte
S Mechiel
SM
Cook
James M
JM
Van Linn
Michael L
ML
Hopkins
Seth C
SC
Olivier
Berend
B
D000208:Acute Disease; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects*; D002243:Carbolines / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects*; D013315:Stress, Psychological / Q000503:physiopathology* / Q000523:psychology*; D013686:Telemetry; D000077334:Zolpidem
D000777:Anesthetics; D014151:Anti-Anxiety Agents; D002243:Carbolines; D002492:Central Nervous System Depressants; D018682:GABA Agents; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives; D007555:Isoxazoles; D011725:Pyridines; D011963:Receptors, GABA-A; D000431:Ethanol; D000077334:Zolpidem; C043232:tert-butyl beta-carboline-3-carboxylate; C015542:gaboxadol; D003975:Diazepam