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B. B. FREDHOLM ANAL. REAL ACAD. NAL. FARM.

Persson; 2001). This agrees with the known effects of caffeine and other
adenosine receptor antagonists. By contrast, potassium excretion and
glomerular filtration rate was unaltered. Most importantly,
tubuloglomerular feedback is completely eliminated in A1R -/- mice
(Brown, Ollerstam, Johansson, Skött, Fredholm and Persson; 2001).
These results emphasize that renal A1 receptors constitute important drug
targets.

Knock-out mice can be used not only to determine the role(s) of a
particular gene product in physiology and pathophysiology, but also to
determine the selectivity of drugs. So far we have finished a study that
demonstrates that at least some of the effects of ATP (and other adenine
nucleotides) in the hippocampus are in fact mediated by A1 receptors,
since the responses are completely eliminated in A1R -/- mouse
hippocampi. It will be important in the future to perform similar studies in
other tissues, since adenine nucleotides are so very rapidly broken down
at cell membranes generating high local concentrations of adenosine

REFERENCES

(1) ÅDÉN, U., HERLENIUS, E., TANG, L.-Q. AND FREDHOLM, B.B. (2000) Maternal
caffeine intake has minor effects on adenosine receptor ontogeny in the rat brain.
Pediat Res 48: 177-83

(2) ALEXANDER, S.P. AND REDDINGTON, M. (1989) The cellular localization of
adenosine receptors in rat striatum. Neuroscience 28: 645-51

(3) ARSLAN, G. AND FREDHOLM, B.B. (2000) Stimulatory and inhibitory effects of
adenosine A2A receptors on nerve growth factor-induced phosphorylation of
extracellular regulated kinases 1/2 in PC12 cells. Neurosci Lett 292: 183-6

(4) ATKINSON, M.R., TOWNSEND-NICHOLSON, A., NICHOLL, J.K., SUTHERLAND, G.R.
AND SCHOLFIELD, P.R. (1997) Cloning, characterisation and chromosomal
assignment of the human adenosine A3 receptor (ADORA3) gene. Neurosci Res
29: 73-9

(5) AUGOOD, S.J. AND EMSON, P.C. (1994) Adenosine A2a receptor mRNA is
expressed by enkephalin cells but not by somatostatin cells in rat striatum: a co-
expression study. Brain Res Mol Brain Res 22: 204-10

(6) BODAS, E., ALEU, J., PUJOL, G., MARTIN-SATUÉ, M., MARSAL, J. AND
SOLSONA, C. (2000) ATP crossing the cell plasma membrane generates an ionic
current in xenopus oocytes. J Biol Chem 275: 20268-73

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