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VOL. 69 (4) ADENOSINE RECEPTORS

increase in motor activity that accompanies transition from light to dark is
reduced in the knockout mice (Giménez-Llort et al.; 2002). Surprisingly,
A1R +/- mice were in this regard indistinguishable from wild-type
animals. However, exploratory activity (assayed in the open field test and
the hole-board) tended to be increased in the heterozygotes (Giménez-
Llort et al.; 2002). This would tally with the known stimulatory effect of
methylxanthines, including caffeine (Fredholm, Bättig, Holmén, Nehlig
and Zvartau; 1999).

The A1R -/- showed increased anxiety using two commonly used tests,
the elevated plus maze and the dark-light box (Giménez-Llort et al.;
2002). This is interesting because hyperanxiety was also observed in A2A
-/- mice (Ledent et al.; 1997). Future experiments will tell if the traits in
the two strains is synergistic. It is also interesting to compare with the fact
that high doses of caffeine that acts on A1 and A2A receptors produces
anxiety in animals and man (Fredholm, Bättig, Holmén, Nehlig and
Zvartau; 1999). Using the resident intruder test A1R -/- mice also
exhibited increased aggressiveness (Giménez-Llort et al.; 2002), again a
trait also observed in A2A -/- mice (Ledent et al.; 1997). By contrast, no
effect was observed when examining memory functions with the Morris
water maze.

Using the hippocampal slice preparation the inhibitory adenosine effects
were shown to be eliminated in A1R -/- mice (Johansson, Halldner,
Dunwiddie, Masino, Poelchen, Giménez-Llort, Escorihuela, Fernández-
Teruel, Wiesenfeld-Hallin, Xu, Hårdemark, Betsholtz, Herlenius and
Fredholm; 2001). This is an important finding since it shows that there are
no important effects mediated via any of the other receptors in this
preparation, despite the fact that important effects of both A2A (Sebastiao
and Ribeiro; 1996) and A3 receptors (Dunwiddie, Diao, Kim, Jiang and
Jacobson; 1997) has been reported. Another important finding was that
the dose-response curve for adenosine was shifted significantly (two-fold)
to the left in A1R +/- mice, which possess almost exactly half the normal
number of receptors. This emphasises the important general point that
potency of adenosine analogues is strongly dependent on the number of
receptors. There were no adaptive changes in responses to GABAB
receptor activation or any adaptive changes in A2A receptors.

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