Adenosine receptor blockade reverses hypophagia and enhances locomotor activity of dopamine-deficient mice
AUTOR(ES)
Kim, Douglas S.
FONTE
The National Academy of Sciences
RESUMO
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 A2A receptors induced feeding and locomotion in mutants much more effectively than an A1 receptor antagonist. l-dopa-elicited feeding and hyperlocomotion were reduced in mutants treated with an A1 receptor agonist, whereas an A2A 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 A2A receptor signaling. This study of a genetic model of dopamine depletion provides evidence that A2A receptor antagonists could ameliorate the hypokinetic symptoms of advanced Parkinson's disease patients without inducing excessive motor activity.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=298775Documentos Relacionados
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