Physiological roles of A1 and A2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine

Abstract

Heart rate (HR), body temperature (Temp), locomotor activity (LA), and oxygen consumption (O₂C) were studied in awake mice lacking one or both of the adenosine A₁ or A_2A receptors (A₁R or A_2AR, respectively) using telemetry and respirometry, before and after caffeine administration. All parameters were lower during day than night and higher in females than males. When compared with wild-type (WT) littermates, HR was higher in male A₁R knockout (A₁RKO) mice but lower in A_2ARKO mice and intermediate in A₁-A_2AR double KO mice. A single dose of an unselective β-blocker (timolol; 1 mg/kg) abolished the HR differences between these genotypes. Deletion of A₁Rs had little effect on Temp, whereas deletion of A_2ARs increased it in females and decreased it in males. A₁-A_2ARKO mice had lower Temp than WT mice. LA was unaltered in A₁RKO mice and lower in A_2ARKO and A₁-A_2ARKO mice than in WT mice. Caffeine injection increased LA but only in mice expressing A_2AR. Caffeine ingestion also increased LA in an A_2AR-dependent manner in male mice. Caffeine ingestion significantly increased O₂C in WT mice, but less in the different KO mice. Injection of 30 mg/kg caffeine decreased Temp, especially in KO mice, and hence in a manner unrelated to A₁R or A_2AR blockade. Selective A_2B antagonism had little or no effect. Thus A₁R and A_2AR influence HR, Temp, LA, and O₂C in mice in a sex-dependent manner, indicating effects of endogenous adenosine. The A_2AR plays an important role in the modulation of O₂C and LA by acute and chronic caffeine administration. There is also evidence for effects of higher doses of caffeine being independent of both A₁R and A_2AR.