Torpor in hibernating mammals defines the nadir in mammalian metabolic demand and body temperature that accommodates seasonal periods of reduced energy availability. The mechanism of metabolic suppression during torpor onset is unknown although the central nervous system (CNS) is a key regulator of torpor. Seasonal hibernators such as the arctic ground squirrel (AGS) display torpor only during the winter, hibernation season. The seasonal character of hibernation thus provides a clue to its regulation. In the present study we delivered adenosine receptor agonists and antagonists into the lateral ventricle of AGS at different times of the year while monitoring the rate of O2 consumption and core body temperature as indicators of torpor. The A1 antagonist, cyclopentyltheophylline (CPT) reversed spontaneous entrance into torpor. The adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA) induced torpor in 6 out of 6 AGS tested during the mid-hibernation season, 2 out of 6 AGS tested early in the hibernation season and none of the 6 AGS tested during the summer, off-season. CHA-induced torpor within the hibernation season was specific to A1AR activation; the A3AR agonist 2-Cl-IB MECA failed to induce torpor and the A2aR antagonist MSX-3, failed to reverse spontaneous onset of torpor. CHA-induced torpor was similar to spontaneous entrance into torpor. These results show that metabolic suppression during torpor onset is regulated within the CNS via A1AR activation and requires a seasonal switch in the sensitivity of purinergic signaling.

A1 adenosine receptor (A1AR) activation within the central nervous system induces torpor, but in obligate hibernators such as the arctic ground squirrel (AGS; Urocitellus parryii), A1AR stimulation induces torpor only during the hibernation season, suggesting a seasonal increase in sensitivity to A1AR signaling. The purpose of this research was to investigate the relationship between body temperature (Tb) and sensitivity to an adenosine A1 receptor agonist in AGS. We tested the hypothesis that increased sensitivity in A1AR signaling would lead to lower Tb in euthermic animals during the hibernation season when compared with the summer season. We further predicted that if a decrease in euthermic Tb reflects increased sensitivity to A1AR activation, then it should likewise predict spontaneous torpor. We used subcutaneous IPTT-300 transponders to monitor Tb in AGS housed under constant ambient conditions (12:12 L:D, 18 °C) for up to 16 months. These animals displayed an obvious rhythm in euthermic Tb that cycled with a period of approximately 8 months. Synchrony in the Tb rhythm within the group was lost after several months of constant L:D conditions; however, individual rhythms in Tb continued to show clear sine wave–like waxing and waning. AGS displayed spontaneous torpor only during troughs in euthermic Tb. To assess sensitivity to A1AR activation, AGS were administered the A1AR agonist N6-cyclohexyladenosine (CHA, 0.1 mg/kg, ip), and subcutaneous Tb was monitored. AGS administered CHA during a seasonal minimum in euthermic Tb showed a greater drug-induced decrease in Tb (1.6 ± 0.3 °C) than did AGS administered CHA during a peak in euthermic Tb (0.4 ± 0.3 °C). These results provide evidence for a circannual rhythm in Tb that is associated with increased sensitivity to A1AR signaling and correlates with the onset of torpor.

Therapeutic hypothermia (TH) improves prognosis after cardiac arrest; however, thermoregulatory responses such as shivering complicate cooling. Hibernators exhibit a profound and safe reversible hypothermia without any cardiovascular side effects by lowering the shivering threshold at low ambient temperatures (Ta). Activation of adenosine A1 receptors (A1ARs) in the central nervous system (CNS) induces hibernation in hibernating species and a hibernation-like state in rats, principally by attenuating thermogenesis. Thus, we tested the hypothesis that targeted activation of the central A1AR combined with a lower Ta would provide a means of managing core body temperature (Tb) below 37 °C for therapeutic purposes. We targeted the A1AR within the CNS by combining systemic delivery of the A1AR agonist 6N-cyclohexyladenosine (CHA) with 8-(p-sulfophenyl) theophylline (8-SPT), a nonspecific adenosine receptor antagonist that does not readily cross the blood–brain barrier. Results show that CHA (1 mg/kg) and 8-SPT (25 mg/kg), administered intraperitoneally every 4 h for 20 h at a Ta of 16 °C, induce and maintain the Tb between 29 and 31 °C for 24 h in both naïve rats and rats subjected to asphyxial cardiac arrest for 8 min. Faster and more stable hypothermia was achieved by continuous infusion of CHA delivered subcutaneously via minipumps. Animals subjected to cardiac arrest and cooled by CHA survived better and showed less neuronal cell death than normothermic control animals. Central A1AR activation in combination with a thermal gradient shows promise as a novel and effective pharmacological adjunct for inducing safe and reversible targeted temperature management.

Rationale Evidence links longevity to dietary restriction (DR). A decrease in body temperature (Tb) is thought to contribute to enhanced longevity because lower Tb reduces oxidative metabolism and oxidative stress. It is as yet unclear how DR decreases Tb. Objective Here, we test the hypothesis that prolonged DR decreases Tb by sensitizing adenosine A1 receptors (A1AR) and adenosine-induced cooling. Methods and results Sprague–Dawley rats were dietary restricted using an every-other-day feeding protocol. Rats were fed every other day for 27 days and then administered the A1AR agonist, N6-cyclohexyladenosine (CHA; 0.5 mg/kg, i.p.). Respiratory rate (RR) and subcutaneous Tb measured using IPTT-300 transponders were monitored every day and after drug administration. DR animals displayed lower RR on day 20 and lower Tb on day 22 compared to animals fed ad libitum and displayed a larger response to CHA. In all cases, RR declined before Tb. Contrary to previous reports, a higher dose of CHA (5 mg/kg, i.p.) was lethal in both dietary groups. We next tested the hypothesis that sensitization to the effects of CHA was due to increased surface expression of A1AR within the hypothalamus. We report that the abundance of A1AR in the membrane fraction increases in hypothalamus, but not cortex of DR rats. Conclusion These results suggest that every-other-day feeding lowers Tb via sensitization of thermoregulatory effects of endogenous adenosine by increasing surface expression of A1AR. Discussion Evidence that diet can modulate purinergic signaling has implications for the treatment of stroke, brain injury, epilepsy, and aging.

High-dose valproic acid combined with hypothermic-targeted temperature management prevents postcardiac arrest seizures and improves survival. It remains to be determined if the mechanism of seizure prevention is through the antiepileptic effect of valproic acid or direct neuroprotection. Overall, the combination of high-dose valproic acid and hypothermic-targeted temperature management remains a promising strategy to improve cardiac arrest outcomes.

Hibernation is an adaptation to overcome periods of resource limitation often associated with extreme climatic conditions. The hibernation season consists of prolonged bouts of torpor that are interrupted by brief interbout arousals. Physiological mechanisms regulating spontaneous arousals are poorly understood, but may be related to a need for gluconeogenesis or elimination of metabolic wastes. Glutamate is derived from glutamine through the glutamate-glutamine cycle and from glucose via the pyruvate carboxylase pathway when nitrogen balance favors formation of glutamine. The present study tests the hypothesis that activation of NMDA type glutamate receptors (NMDAR) maintains torpor in arctic ground squirrel (AGS; Urocitellus parryii).Administration of NMDAR antagonists MK-801 (5mg/kg,ip) that crosses blood-brain barrier and AP5 (5mg/kg,ip) that does not cross the blood brain barrier induced arousal in AGS. Central administration of MK-801 (0.2, 2, 20 or 200 μg; icv) to hibernating AGS failed to induce arousal. Results suggest that activation of NMDAR at a peripheral or circumventricular site is necessary to maintain prolonged torpor and that a decrease in glutamate at these sites may contribute to spontaneous arousal in AGS.

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