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 (T1) and stress-induced body temperature (T2) are measured, predicts anxiolytic drug effect. Serotonergic drugs alter these responses and here, we studied the role of 5-HT1A receptors in stress-induced hyperthermia by using 5-HT1A 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 α2 subunit containing GABAA receptors, including diazepam and L838,417, result in reduced ΔT (ΔT = T2 − T1). The α1 subunit containing GABAA receptor was found to be primarily involved in regulation of basal body temperature T1 and its stimulation can induce hypothermia. In addition, stimulation of 5-HT1A receptors by buspirone results in a reduced ΔT, while stimulation of 5-HT7 receptors primarily results in hypothermia. The null mutation of 5-HT1A 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-HT1A receptor and genetic background and demonstrates the importance of selecting the background strain in a receptor knockout model.