BACKGROUND: The marked improvement in outcome following induction of hypothermia after cardiac arrest has spurred the search for better methods to induce cooling. A regulated decrease in core temperature mediated by a drug-induced reduction in the set point for thermoregulation may be an ideal means of inducing hypothermia. To this end, the exploratory drug HBN-1 was assessed as a means to induce mild and prolonged hypothermia. METHODS: Free moving rats were infused i.v. for 12 hours with: a vehicle at room temperature (normothermia), a vehicle chilled to 4°C (forced hypothermia), or HBN-1 (mixture of ethanol, lidocaine, and vasopressin) at room temperature. Core (intra-abdominal) temperature (Tc) was measured telemetrically, tail skin temperature (Ttail) by infrared thermography, metabolic rate (MR) was estimated with indirect calorimetery, and shivering was scored visually. RESULTS: HBN-1 elicited a reduction in Tc from 37.5°C to 34°C within 80 minutes after initiation of the infusion; Tc was maintained between 33°C and 34°C for more than 13 hours. HBN-1 infusion was associated with a reduction in MR (p=0.0006), a slight reduction in Ttail, and no evidence of shivering (p<0.001). The forced hypothermia group displayed shivering (p<0.001), a significant increase in MR, and a decrease in Ttail, indicative of peripheral vasoconstriction to reduce heat loss. CONCLUSION: HBN-1 infusion induced a mild and prolonged hypothermia in free moving, unanesthetized rats characterized by modulation of thermoeffectors to reduce heat gain and increase heat loss. HBN-1 thus appears to elicit regulated hypothermia and may provide a new method for achieving a prolonged state of therapeutic hypothermia.