Effects of genetic background and null mutation of 5-HT1A receptors on basal and stress-induced body temperature: modulation by serotonergic and GABAA-ergic drugs.

Abstract

The stress-induced hyperthermia procedure, in which effects of drugs on basal (T(1)) and stress-induced body temperature (T(2)) are measured, predicts anxiolytic drug effect. Serotonergic drugs alter these responses and here, we studied the role of 5-HT(1A) receptors in stress-induced hyperthermia by using 5-HT(1A) receptor knockout mice. Three strains (129/Sv, Swiss Webster and C57Bl6) were used because genetic background can significantly modulate the null phenotype. We found that GABA-ergic drugs with an anxiolytic profile and stimulate alpha(2) subunit containing GABA(A) receptors, including diazepam and L838,417, result in reduced DeltaT (DeltaT=T(2)-T(1)). The alpha(1) subunit containing GABA(A) receptor was found to be primarily involved in regulation of basal body temperature T(1) and its stimulation can induce hypothermia. In addition, stimulation of 5-HT(1A) receptors by buspirone results in a reduced DeltaT, while stimulation of 5-HT(7) receptors primarily results in hypothermia. The null mutation of 5-HT(1A) receptors resulted in differences in drug-sensitivity that was further modulated by the genetic background. In particular, the null mutation on the SW and C57Bl6 backgrounds resulted in differential diazepam/L838,417 and 5-CT responses respectively. This indicates an interaction between the 5-HT(1A) receptor and genetic background and demonstrates the importance of selecting the background strain in a receptor knockout model.

• Authors: Meg Van Bogaert, Ronald Oosting, Miklos Toth, Lucianne Groenink, Ruud van Oorschot, Berend Olivier
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 550 Issue 1-3 Pg. 84-90 (Nov 21 2006) ISSN: 0014-2999 [Print] Netherlands
• PMID: 17022970 (Publication Type: Journal Article)

Chemical References

• Fluorobenzenes
• GABA Agonists
• GABA Modulators
• Pyridines
• Receptors, GABA-A
• Serotonin Agents
• Serotonin Receptor Agonists
• Triazoles
• Receptor, Serotonin, 5-HT1A
• Serotonin
• Flumazenil
• Zolpidem
• L 838,417
• 5-carboxamidotryptamine
• Diazepam
• Buspirone

Topics

• Animals
• Body Temperature (drug effects, genetics, physiology)
• Body Temperature Regulation (drug effects)
• Buspirone (pharmacology)
• Diazepam (pharmacology)
• Fever (physiopathology)
• Flumazenil (pharmacology)
• Fluorobenzenes (pharmacology)
• GABA Agonists (pharmacology)
• GABA Modulators (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Pyridines (pharmacology)
• Receptor, Serotonin, 5-HT1A (drug effects, genetics, physiology)
• Receptors, GABA-A (drug effects)
• Serotonin (analogs & derivatives, pharmacology)
• Serotonin Agents (pharmacology)
• Serotonin Receptor Agonists (pharmacology)
• Stress, Psychological (physiopathology)
• Triazoles (pharmacology)
• Zolpidem