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

mediates the A2A effects. If it proves possible to find agents that
selectively affects A2A-Golf more selective drugs may be found.

Physiology of adenosine A1 receptors as determined from studies
using knock out mice
Even though quite selective agonists and antagonists are available for
adenosine A1 receptors (Fredholm, IJzerman, Jacobson, Klotz and
Linden; 2001), and consequently much is known about their role in
physiology and pathophysiology we embarked on a classical gene knock
out strategy. The second coding exon was targeted as described
(Johansson, Halldner, Dunwiddie, Masino, Poelchen, Giménez-Llort,
Escorihuela, Fernández-Teruel, Wiesenfeld-Hallin, Xu, Hårdemark,
Betsholtz, Herlenius and Fredholm; 2001) and experiments were
conducted on littermates from matings of heterozygote animals (A1R +/-)
with a mixed C57Bl6/129OlaHsd background.

The offspring showed the expected frequency (1/4 A1R +/+; 2/4 A1R +/-
and 1/4 A1R -/-). There were no clear differences in the growth and
maturation over the first five months between genotypes (Johansson,
Halldner, Dunwiddie, Masino, Poelchen, Giménez-Llort, Escorihuela,
Fernández-Teruel, Wiesenfeld-Hallin, Xu, Hårdemark, Betsholtz,
Herlenius and Fredholm; 2001), but subsequently +/- and, especially, -/-
mice tended to die faster than their +/+ littermates (Giménez-Llort,
Fernández-Teruel, Escorihuela, Fredholm, Tobena, Pekny and Johansson;
2002). So far we have not observed any major differences in fertility
between genotypes, even though there is evidence that the A1 receptor is
involved in sperm capacitation.

A1R +/- and -/- mice showed no gross behavioural abnormalities.
However, their grip strength, as judged by the so called wire hanger test,
was reduced (Giménez-Llort et al.; 2002). This was somewhat surprising
given the evidence that methylxanthines in doses that predominantly
affect adenosine receptors appear, if anything, to increase muscle
strength.

Although overall locomotor activity was unaltered in A1R -/- mice
(Johansson, Halldner, Dunwiddie, Masino, Poelchen, Giménez-Llort,
Escorihuela, Fernández-Teruel, Wiesenfeld-Hallin, Xu, Hårdemark,
Betsholtz, Herlenius and Fredholm; 2001), we have found that the

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