A1 and A3 Adenosine receptors mediate hypothermia via distinct mechanisms

Authors

• JL Carlin
• DK Tosh
• A Panyutin
• R Pinol
• KA Jacobson
• O Gavrilova
• ML Reitman

Abstract

Introduction: Pharmacological activation of adenosine receptors in mice and rats causes torpor, which is characterized by reduced body temperature (hypothermia) and reduced physical activity. The current experiments examined the role of adenosine agonists at the A1AR and A3AR in eliciting these effects. Methods: Adenosine agonists were administered intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.) and core body temperature and physical activity were monitored by telemetry in freely active wild type, Adora1-/-, and Adora3-/- mice. Results: All agonists tested i.p. (MRS5474; N6-cyclopentyladenosine, CPA; N6-cyclohexyladenosine, CHA; 5’-chloro-5’ deoxy-ENBA, Cl-ENBA; and MRS5698) caused dose-dependent hypothermia and decreased physical activity in wild type mice. Hypothermia induced by A3AR agonist MRS5698 was abolished in Adora3-/-, but not in Adora1-/-, mice, demonstrating that MRS5698 (10 mg/kg) is selective for A3AR. A3AR agonist, but not A1AR agonists induced hypothermia was prevented by pretreatment with histamine H1 antagonists (i.p.). Interestingly, the hypothermia elicited by commonly used A1AR agonists CPA and CHA was at least partially reduced in the Adora3-/- . We found CPA (0.3 mg/kg), CHA (0.05 mg/kg), and Cl-ENBA (3 mg/kg), at doses that are in the range typically used to study A1AR function, to also cause hypothermia via an A3AR mechanism. Conclusions: These results demonstrate that activation of both A1AR and A3AR can cause hypothermia through independent mechanisms. Our results also suggest that nucleoside derivatives commonly used as selective A1AR agonists may also activate the A3AR in vivo, at the doses used to produce hypothermia.

Scientific Focus Area: Neuroscience

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