5-HT1A receptor blockade reverses GABAA receptor α3 subunit-mediated anxiolytic effects on stress-induced hyperthermia

• Published in: Psychopharmacologia Vol. 211; no. 2; pp. 123 - 130
• Main Authors: Vinkers, Christiaan H., van Oorschot, Ruud, Korte, S. Mechiel, Olivier, Berend, Groenink, Lucianne
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-08-2010; Springer
• Subjects: Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Medical sciences; Neuropharmacology; Neurosciences; Original Investigation; Pharmacology. Drug treatments; Pharmacology/Toxicology; Psychiatry; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; TP003; alpha 3; Interaction; Serotonin antagonist; Benzodiazepine; Zolpidem; Serotonergic; alpha3; WAY-100635; Anxiety; Stress; WAY100,635; Agonist; Psychotropic; Gabaergic agonist; Hypnotic; Benzodiazepine receptor; Subunit; Imidazopyridine derivatives; 5-HT1A Serotonine receptor; Tranquillizer; Benzodiazepine derivatives; Gabaergic receptor A; Induced hyperthermia
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-010-1895-7

Rationale
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.
Objectives
The main aim of the present study was to investigate whether the anxiolytic effects of (non-)selective α 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-α-subunit selective GABA
A
receptor agonist diazepam (1–4 mg/kg) and the GABA
A
receptor α
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 α
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 α-subunits and 5-HT
1A
receptor activation in the SIH response. Specifically, our data indicate that benzodiazepines affect serotonergic signaling via GABA
A
receptor α
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.