Mice heterozygous for both A1 and A(2A) adenosine receptor genes show similarities to mice given long-term caffeine.
Caffeine is believed to exert its stimulant effects by blocking A(2A) and A(1) adenosine receptors (A(2A)R and A(1)R). Although a genetic knockout of A(2A)R 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 A(1)Rs and A(2A)Rs, achieved by deleting one of the two copies of the A(1)R and A(2A)R genes, would mimic some aspects of long-term caffeine ingestion. The A(1)R and A(2A)R double heterozygous (A(1)R-A(2A)R dHz) mice indeed had approximately one-half the number of A(1)R and A(2A)R, and there were little compensatory changes in A(2B) or A(3) adenosine receptor (A(2B)R or A(3)R) expression. The ability of a stable adenosine analog to activate receptors was shifted to the right by caffeine and in A(1)R-A(2A)R dHz tissue. Caffeine (0.3 g/l in drinking water for 7-10 days) and A(1)R-A(2A)R 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 A(1)R-A(2A)R 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 A(1)R and A(2A)R.
Yang
Jiang-Ning
JN
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. jiangning.yang@ki.se
Björklund
Olga
O
Lindström-Törnqvist
Karin
K
Lindgren
Eva
E
Eriksson
Therese M
TM
Kahlström
Johan
J
Chen
Jiang-Fan
JF
Schwarzschild
Michael A
MA
Tobler
Irene
I
Fredholm
Bertil B
BB
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002110:Caffeine / Q000008:administration & dosage*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D006579:Heterozygote; D007274:Injections, Intraperitoneal; D008066:Lipolysis / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010641:Phenotype; D043682:Receptor, Adenosine A1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D043683:Receptors, Adenosine A2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000697:Central Nervous System Stimulants; D043682:Receptor, Adenosine A1; D043683:Receptors, Adenosine A2; D002110:Caffeine