5-HT1A receptor blockade reverses GABA(A) receptor alpha3 subunit-mediated anxiolytic effects on stress-induced hyperthermia.
BACKGROUND
Stress-related disorders are associated with dysfunction of both serotonergic and GABAergic pathways, and clinically effective anxiolytics act via both neurotransmitter systems. As there is evidence that the GABA(A) and the serotonin receptor system interact, a serotonergic component in the anxiolytic actions of benzodiazepines could be present.


OBJECTIVE
The main aim of the present study was to investigate whether the anxiolytic effects of (non-)selective alpha subunit GABA(A) receptor agonists could be reversed with 5-HT(1A) receptor blockade using the stress-induced hyperthermia (SIH) paradigm.


RESULTS
The 5-HT(1A) receptor antagonist WAY-100635 (0.1-1 mg/kg) reversed the SIH-reducing effects of the non-alpha-subunit selective GABA(A) receptor agonist diazepam (1-4 mg/kg) and the GABA(A) receptor alpha(3)-subunit selective agonist TP003 (1 mg/kg), whereas WAY-100635 alone was without effect on the SIH response or basal body temperature. At the same time, co-administration of WAY-100635 with diazepam or TP003 reduced basal body temperature. WAY-100635 did not affect the SIH response when combined with the preferential alpha(1)-subunit GABA(A) receptor agonist zolpidem (10 mg/kg), although zolpidem markedly reduced basal body temperature.


CONCLUSIONS
The present study suggests an interaction between GABA(A) receptor alpha-subunits and 5-HT(1A) receptor activation in the SIH response. Specifically, our data indicate that benzodiazepines affect serotonergic signaling via GABA(A) receptor alpha(3)-subunits. Further understanding of the interactions between the GABA(A) and serotonin system in reaction to stress may be valuable in the search for novel anxiolytic drugs.
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Sorbonnelaan 16, 3584CA, Utrecht, The Netherlands. c.h.vinkers@uu.nl
Christiaan H
CH
Vinkers
Ruud
R
van Oorschot
S Mechiel
SM
Korte
Berend
B
Olivier
Lucianne
L
Groenink
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D003975:Diazepam / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D018755:GABA Agonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D013315:Stress, Psychological / Q000188:drug therapy* / Q000503:physiopathology; D000077334:Zolpidem
C552286:4,2'-difluoro-5'-(8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo(1,2-a)pyridin-3-yl)biphenyl-2-carbonitrile; D014151:Anti-Anxiety Agents; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; C546241:Gabra1 protein, mouse; C546258:Gabra3 protein, mouse; D007093:Imidazoles; D010879:Piperazines; D011725:Pyridines; D011963:Receptors, GABA-A; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D000077334:Zolpidem; D003975:Diazepam