Hypothermia in mouse is caused by adenosine A and A receptor agonists and AMP via three distinct mechanisms.

Small mammals have the ability to enter torpor, a hypothermic, hypometabolic state, allowing impressive energy conservation. Administration of adenosine or adenosine 5'-monophosphate (AMP) can trigger a hypothermic, torpor-like state. We investigated the mechanisms for hypothermia using telemetric monitoring of body temperature in wild type and receptor knock out (Adora1, Adora3) mice. Confirming prior data, stimulation of the A adenosine receptor (AR) induced hypothermia via peripheral mast cell degranulation, histamine release, and activation of central histamine H receptors. In contrast, AAR agonists and AMP both acted centrally to cause hypothermia. Commonly used, selective AAR agonists, including N-cyclopentyladenosine (CPA), N-cyclohexyladenosine (CHA), and MRS5474, caused hypothermia via both AAR and AAR when given intraperitoneally. Intracerebroventricular dosing, low peripheral doses of Cl-ENBA [(±)-5'-chloro-5'-deoxy-N-endo-norbornyladenosine], or using Adora3 mice allowed selective stimulation of AAR. AMP-stimulated hypothermia can occur independently of AAR, AAR, and mast cells. AAR and AAR agonists and AMP cause regulated hypothermia that was characterized by a drop in total energy expenditure, physical inactivity, and preference for cooler environmental temperatures, indicating a reduced body temperature set point. Neither AAR nor AAR was required for fasting-induced torpor. AAR and AAR agonists and AMP trigger regulated hypothermia via three distinct mechanisms.