Functional uncoupling of adenosine A(2A) receptors and reduced response to caffeine in mice lacking dopamine D2 receptors

Nancy R. Zahniser, Johanna K. Simosky, R. Dayne Mayfield, Cori A. Negri, Taleen Hanania, Gaynor A. Larson, Michele A. Kelly, David K. Grandy, Marcelo Rubinstein, Malcolm J. Low, Bertil B. Fredholm

    Research output: Contribution to journalArticle

    75 Scopus citations

    Abstract

    Dopamine D2 receptors (Rs) and adenosine A(2A)Rs 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 A(2A)R effects would be enhanced in D2R-deficient mice, the A(2A)R 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 A(2A)Rs in the striatum or globus pallidus. However, CGS 21680 significantly stimulated cAMP production only in D2R(+/+) striatal/pallidal slices. This functional uncoupling of A(2A)Rs in the D2R-deficient mice was not explained by reduced expression of G(s), G(olf), 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 A(2A)Rs on striatopallidal neurons and thereby responses to drugs that act on adenosine receptors. They also reinforce the ideas that D2Rs and A(2A)Rs are functionally opposed and that D2R-mediated effects normally predominate.

    Original languageEnglish (US)
    Pages (from-to)5949-5957
    Number of pages9
    JournalJournal of Neuroscience
    Volume20
    Issue number16
    DOIs
    StatePublished - Aug 15 2000

    Keywords

    • Adenosine A(2A) receptor
    • CGS 21680
    • Caffeine
    • D receptor knock-out mouse
    • Dopamine D receptor
    • G(olf)
    • G(s)
    • GABA release
    • Locomotor activity
    • Striatopallidal pathway
    • Type VI adenylyl cyclase
    • [H]CGS 21680
    • [H]SCH 58261
    • c-fos
    • cAMP stimulation
    • mRNA

    ASJC Scopus subject areas

    • Neuroscience(all)

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  • Cite this

    Zahniser, N. R., Simosky, J. K., Mayfield, R. D., Negri, C. A., Hanania, T., Larson, G. A., Kelly, M. A., Grandy, D. K., Rubinstein, M., Low, M. J., & Fredholm, B. B. (2000). Functional uncoupling of adenosine A(2A) receptors and reduced response to caffeine in mice lacking dopamine D2 receptors. Journal of Neuroscience, 20(16), 5949-5957. https://doi.org/10.1523/jneurosci.20-16-05949.2000