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The Journal of Neuroscience, August 15, 2000, 20(16):5949-5957

Functional Uncoupling of Adenosine A_2A Receptors and Reduced Response to Caffeine in Mice Lacking Dopamine D₂ Receptors

Nancy R. Zahniser^{1, 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 A_2ARs 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_2AR effects would be enhanced in D₂R-deficient mice, the A_2AR 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_2ARs in the striatum or globus pallidus. However, CGS 21680 significantly stimulated cAMP production only in D₂R^+/+ striatal/pallidal slices. This functional uncoupling of A_2ARs 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_2ARs on striatopallidal neurons and thereby responses to drugs that act on adenosine receptors. They also reinforce the ideas that D₂Rs and A_2ARs are functionally opposed and that D₂R-mediated effects normally predominate.

Key words: adenosine A_2A 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; G_s; G_olf; type VI adenylyl cyclase; locomotor activity; c-fos

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20165949-09$05.00/0

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