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The Journal of Neuroscience, August 15, 2000, 20(16):5949-5957
Functional Uncoupling of Adenosine A2A Receptors and
Reduced Response to Caffeine in Mice Lacking Dopamine D2
Receptors
Nancy R.
Zahniser1, 2,
Johanna K.
Simosky1,
R.
Dayne
Mayfield1,
Cori A.
Negri1,
Taleen
Hanania1,
Gaynor A.
Larson1,
Michele A.
Kelly3,
David K.
Grandy4,
Marcelo
Rubinstein5,
Malcolm J.
Low3, and
Bertil B.
Fredholm6
1 Department of Pharmacology and
2 Neuroscience Program, University of Colorado Health
Sciences Center, Denver, Colorado 80262, 3 Vollum Institute
for Advanced Biomedical Research and 4 Department of
Physiology and Pharmacology, Oregon Health Sciences University,
Portland, Oregon 97201, 5 INGEBI (CONICET) and
Department of Biology, University of Buenos Aires, Buenos Aires,
Argentina, and 6 Department of Physiology and Pharmacology,
Section of Molecular Neuropharmacology, Karolinska Institutet,
Stockholm, Sweden
Dopamine D2 receptors (Rs) and adenosine
A2ARs are coexpressed on striatopallidal neurons, where
they mediate opposing actions. In agreement with the idea that
D2Rs tonically inhibit GABA release from these neurons,
stimulation-evoked GABA release was significantly greater from
striatal/pallidal slices from D2R null mutant
(D2R /) than from wild-type
(D2R+/+) mice. Release from heterozygous
(D2R+/) slices was intermediate.
However, contrary to predictions that A2AR effects would be
enhanced in D2R-deficient mice, the A2AR agonist CGS 21680 significantly increased GABA release only from D2R+/+ slices. CGS 21680 modulation was
observed when D2Rs were antagonized by raclopride,
suggesting that an acute absence of D2Rs cannot explain the
results. The lack of CGS 21680 modulation in the
D2R-deficient mice was also not caused by a compensatory
downregulation of A2ARs in the striatum or globus pallidus.
However, CGS 21680 significantly stimulated cAMP production only in
D2R+/+ striatal/pallidal slices. This
functional uncoupling of A2ARs in the
D2R-deficient mice was not explained by reduced expression of Gs, Golf, or type VI adenylyl
cyclase. Locomotor activity induced by the adenosine receptor
antagonist caffeine was significantly less pronounced in
D2R/ mice than in
D2R+/+ and
D2R+/ mice, further supporting the
idea that D2Rs are required for caffeine activation.
Caffeine increased c-fos only in
D2R/ globus pallidus. The present
results show that a targeted disruption of the D2R reduces
coupling of A2ARs on striatopallidal neurons and thereby
responses to drugs that act on adenosine receptors. They also reinforce
the ideas that D2Rs and A2ARs are functionally opposed and that D2R-mediated effects normally predominate.
Key words:
adenosine A2A receptor; dopamine
D2 receptor; D2 receptor knock-out mouse; CGS
21680; mRNA; [3H]SCH 58261; [3H]CGS 21680; caffeine; striatopallidal pathway; GABA release; cAMP stimulation; Gs; Golf; type VI adenylyl cyclase; locomotor activity; c-fos
Copyright © 2000 Society for Neuroscience 0270-6474/00/20165949-09$05.00/0
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