Abstract
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(3) adenosine receptor (AR) induced hypothermia via peripheral mast cell degranulation, histamine release, and activation of central histamine H(1) receptors. In contrast, A(1)AR agonists and AMP both acted centrally to cause hypothermia. Commonly used, selective A(1)AR agonists, including N(6)-cyclopentyladenosine (CPA), N(6)-cyclohexyladenosine (CHA), and MRS5474, caused hypothermia via both A(1)AR and A(3)AR when given intraperitoneally. Intracerebroventricular dosing, low peripheral doses of Cl-ENBA [(±)-5'-chloro-5'-deoxy-N(6)-endo-norbornyladenosine], or using Adora3(-/-) mice allowed selective stimulation of A(1)AR. AMP-stimulated hypothermia can occur independently of A(1)AR, A(3)AR, and mast cells. A(1)AR and A(3)AR 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 A(1)AR nor A(3)AR was required for fasting-induced torpor. A(1)AR and A(3)AR agonists and AMP trigger regulated hypothermia via three distinct mechanisms.