Institution: | aSection of Psychopharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, The Netherlands bBehavioural Genomics section, Rudolf Magnus Institute of Neuroscience, Utrecht University, The Netherlands cMedical College of Cornell University, New York, USA dDepartment of Psychiatry, Yale University School of Medicine, New Haven, USA |
Abstract: | 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 2 subunit containing GABAA receptors, including diazepam and L838,417, result in reduced ΔT (ΔT = T2 ? T1). The 1 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. |