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.
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.
Van Bogaert
Meg
M
Section of Psychopharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, The Netherlands. M.J.V.VanBogaert@pharm.uu.nl
Oosting
Ronald
R
Toth
Miklos
M
Groenink
Lucianne
L
van Oorschot
Ruud
R
Olivier
Berend
B
D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001833:Body Temperature Regulation / Q000187:drug effects; D002065:Buspirone / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D005334:Fever / Q000503:physiopathology; D005442:Flumazenil / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D011963:Receptors, GABA-A / Q000187:drug effects*; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013315:Stress, Psychological / Q000503:physiopathology*; D014230:Triazoles / Q000494:pharmacology; D000077334:Zolpidem
D005464:Fluorobenzenes; D018755:GABA Agonists; D018757:GABA Modulators; D011725:Pyridines; D011963:Receptors, GABA-A; D018490:Serotonin Agents; D017366:Serotonin Receptor Agonists; D014230:Triazoles; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D005442:Flumazenil; D000077334:Zolpidem; C409903:L 838,417; C047087:5-carboxamidotryptamine; D003975:Diazepam; D002065:Buspirone