Hibernation is a fully reversible condition characterized by hypometabolism and deep hypothermia. Core body temperature (Tb) in hibernating ground squirrels decreases to within 1 or 2°C of ambient temperature (Ta) and can fall to as low as -3°C (Barnes, 1989). In recent work, we showed that the arctic ground squirrel enters hibernation through activation of CNS adenosine A1 receptors (A1AR) (Jinka et al., 2011), in a manner consistent with the inhibition of thermogenesis. Similarly, A1AR agonists in nonhibernating species mediate a hypothermic response through effects on the CNS (Anderson et al., 1994). Several aspects of the hibernation phenotype have therapeutic implications (Drew et al., 2001). Here we harness mechanisms hibernating animals use to cool during onset of torpor for therapeutic hypothermia (TH). TH is the only treatment known to improve prognosis for cardiac arrest patients (Hypothermia-after-Cardiac-Arrest-Study-Group, 2002). Thermoregulatory responses such as shivering, however, complicate cooling in comatose cardiac arrest patients and limit efficacy of TH in conscious stroke patients (Zgavc et al., 2011). Stimulating CNS A1AR to suppress thermogenesis mimics the process hibernating animals use to cool during onset of hibernation. Here we describe a strategy of targeted temperature management based on principles of CNS control of hibernation. All work on animals was approved by the UAF IACUC. In these experiments the A1AR agonist 6N-cyclohexyladenosine (CHA) was administered to rats (male, 69-75 days old; 250-350g, n=6) at a Ta of 16°C to lower body temperature. 8-(p-Sulfophenyl)theophylline (8-SPT), a nonselective adenosine receptor antagonist that does not cross the blood brain barrier was administered prior to CHA to mitigate direct effects of CHA on the heart. Asphyxial cardiac arrest was performed as before (Dave et al., 2006). Rats were anesthetized with 4% isoflurane and a 30:70 mixture of O2 and N2O followed by endotracheal intubation and mechanical ventilation. Vecuronium (1mg/kg) was injected iv and apnea induced by disconnecting the ventilator from the endotracheal tube to induce cardiac arrest. Adequacy of isoflurane anesthesia was assessed prior to onset of neuromuscular blockade and maintained at this level for less than 10 min before cardiac arrest induced a comatose state. Resuscitation was initiated after 8 min of apnea. Rats resuscitated within 120 sec were screened for additional inclusion criteria and randomly allocated to TH or normothermic control (NC) treatment groups. Subcutaneous body temperature was monitored using IPTT-300 transponders (Biomedic Data Systems, Inc., USA). Treatments: The TH group was administered 8-SPT (25mg/kg,ip) 15min prior to CHA 1mg/kg,ip. This drug combination was administered 6 times at 4h intervals to rats held at a Ta of 16°C. The NC group was administered 8-SPT vehicle (saline) 15 min prior to CHA vehicle (0.1M phosphate buffer) in the same manner as 8-SPT/CHA and held in a neonatal incubator set to 29°C. Treatment commenced 70min after restoration of spontaneous circulation (ROSC) and continued for 24h. The final injection of CHA was administered at 20h and rats rewarmed at 24h by returning to the home room at a Ta of 20°C. Histology: 7 days after ROSC rats were perfused as before (Dave et al., 2006) and hippocampal CA1 regions examined for histopathology. Results: Mean ± SEM Tb was 33.5°C±0.07 and 33.5°C±0.14 in the NC and TH groups at onset of treatment. Tb in all 3 NC rats increased to 36.5-36.8 within 15 min of placement at 29°C and remained between 36.2 and 37.3°C until death. Only 1 rat in the NC group survived to 7 days. The remaining 2 rats died between 13-18h after ROSC. Tb in the 3 rats treated with TH decreased to 31.0 to 31.6°C within 3h of CHA injection and remained between 31.8 and 29.2°C for 24h before rewarming. Rats rewarmed within 5h after transfer to a Ta of 20°C, 4h after the last injection of CHA. Qualitative assessment of CA1 histopathology in TH treated rats indicated an absence of pathology; the CA1 in TH treated rats appeared similar to CA1 in naïve rats. Quantitative analysis by an observer unaware of treatment indicated that the number of healthy neurons in CA1 of TH treated rats was not statistically different from naïve rats, p=0.154, n=3-5. Conclusion: Activation of CNS A1AR in animals exposed to a thermal gradient (Ta of 16°C) is a simple and effective means of inducing TH. Animals cooled in this manner survived cardiac arrest better than control treated animals and showed no evidence of histopathology in CA1 when compared to naïve rats. These results suggest that by mimicking mechanisms used by hibernating animals to cool it will be possible to administer therapeutic hypothermia in a highly effective, noninvasive and reversible manner.