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Mice heterozygous for both A₁ and A_2A adenosine receptor genes show similarities to mice given long-term caffeine

¹Department of Physiology and Pharmacology and ²Department of Surgical Science, Karolinska Institutet, Stockholm, Sweden; ³Department of Neurology, Boston University School of Medicine, Boston; ⁴Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, Massachusetts; and ⁵Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland

Submitted 29 July 2008 ; accepted in final form 23 November 2008

Caffeine is believed to exert its stimulant effects by blocking A_2A and A₁ adenosine receptors (A_2AR and A₁R). Although a genetic knockout of A_2AR eliminates effects of caffeine, the phenotype of the knockout animal does not resemble that of caffeine treatment. In this study we explored the possibility that a mere reduction of the number of A₁Rs and A_2ARs, achieved by deleting one of the two copies of the A₁R and A_2AR genes, would mimic some aspects of long-term caffeine ingestion. The A₁R and A_2AR double heterozygous (A₁R-A_2AR dHz) mice indeed had approximately one-half the number of A₁R and A_2AR, and there were little compensatory changes in A_2B or A₃ adenosine receptor (A_2BR or A₃R) expression. The ability of a stable adenosine analog to activate receptors was shifted to the right by caffeine and in A₁R-A_2AR dHz tissue. Caffeine (0.3 g/l in drinking water for 7–10 days) and A₁R-A_2AR dHz genotype increased locomotor activity (LA) and decreased heart rate without significantly influencing body temperature. The acute stimulatory effect of a single injection of caffeine was reduced in A₁R-A_2AR dHz mice and in mice treated long term with oral caffeine. Thus at least some aspects of long-term caffeine use can be mimicked by genetic manipulation of the A₁R and A_2AR.

knockout; locomotor activity; tolerance; receptor binding; lipolysis

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