Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 100, Issue 3, Pages 1346-1351Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.252753799
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Adenosine receptors modulate dopaminergic function by regulating dopamine release in presynaptic neurons and intracellular signaling in postsynaptic striatal neurons. To investigate how adenosine impinges on the action of dopamine in feeding and locomotion, genetically altered, dopamine-deficient mice were treated with adenosine receptor antagonists. Acute administration of the nonselective adenosine receptor antagonist, caffeine (5-25 mg/kg i.p.), reversed the hypophagia of mutant mice and induced hyperactivity in both control and mutant animals. However, caffeine treatment elicited much less hyperactivity in dopamine-deficient mice than did (L)-3,4-dihydroxyphenylalanine ((L)-dopa) administration, which partially restores dopamine content. Caffeine treatment enhanced feeding of (L)-dopa-treated mutants but, unexpectedly, it reduced their hyperlocomotion. Caffeine administration induced c-Fos expression in the cortex of dopamine-deficient mice but had no effect in the striatum by itself. Caffeine attenuated dopamine agonist-induced striatal c-Fos expression. An antagonist selective for adenosine A(2A) receptors induced feeding and locomotion in mutants much more effectively than an A(1) receptor antagonist. (L)-dopa-elicited feeding and hyperlocomotion were reduced in mutants treated with an A(1) receptor agonist, whereas an A(2A) receptor agonist decreased (L)-dopa-induced feeding without affecting locomotion. The observations suggest that the hypophagia and hypoactivity of mutants result not only because of the absence of dopamine but also because of the presence of A(2A) receptor signaling. This study of a genetic model of dopamine depletion provides evidence that A(2A) receptor antagonists could ameliorate the hypokinetic symptoms of advanced Parkinson's disease patients without inducing excessive motor activity.
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