Extracellular
adenosine, a danger signal, can cause
hypothermia. We generated mice lacking neuronal
adenosine A1 receptors (A1AR, encoded by the Adora1 gene) to examine the contribution of these receptors to
hypothermia. Intracerebroventricular injection of the selective A1AR agonist (Cl-ENBA, 5'-chloro-5'-deoxy-N6-endo-norbornyladenosine) produced
hypothermia, which was reduced in mice with deletion of A1AR in neurons. A non-brain penetrant A1AR agonist [SPA, N6-(p-sulfophenyl)
adenosine] also caused
hypothermia, in wild type but not mice lacking neuronal A1AR, suggesting that peripheral neuronal A1AR can also cause
hypothermia. Mice expressing
Cre recombinase from the Adora1 locus were generated to investigate the role of specific cell populations in body temperature regulation. Chemogenetic activation of Adora1-Cre-expressing cells in the preoptic area did not
change body temperature. In contrast, activation of Adora1-Cre-expressing dorsomedial hypothalamus cells increased core body temperature, concordant with agonism at the endogenous inhibitory A1AR causing
hypothermia. These results suggest that A1AR agonism causes
hypothermia via two distinct mechanisms: brain neuronal A1AR and A1AR on neurons outside the blood-brain barrier. The variety of mechanisms that
adenosine can use to induce
hypothermia underscores the importance of
hypothermia in the mouse response to major metabolic stress or injury.