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The Journal of Neuroscience, June 15, 2001, 21(12):4390-4399

G_olf Levels Are Regulated by Receptor Usage and Control Dopamine and Adenosine Action in the Striatum

Denis Hervé¹, Catherine Le Moine², Jean-Christophe Corvol¹, Leonardo Belluscio³, Catherine Ledent⁴, Allen A. Fienberg⁵, Mohamed Jaber⁶, Jeanne-Marie Studler¹, and Jean-Antoine Girault¹

¹ Institut National de la Santé et de la Recherche Médicale (INSERM) U536, Institut du Fer à Moulin, 75005 Paris, France, ² Centre National de la Recherche Scientifique Unité Mixte 5541, Laboratoire d'Histologie-Embryologie, Université Victor Segalen Bordeaux 2, 33076 Bordeaux cedex, France, ³ Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, ⁴ Institut de Recherche Interdisciplinaire en Biologie Humaine et Nucléaire, Université Libre de Bruxelles, Campus Erasme, B-1070 Bruxelles, Belgium, ⁵ Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021, and ⁶ INSERM U259, Institut François Magendie, Université Bordeaux II, 33077 Bordeaux cedex, France

In the striatum, dopamine D₁ and adenosine A_2A receptors stimulate the production of cAMP, which is involved in neuromodulation and long-lasting changes in gene expression and synaptic function. Positive coupling of receptors to adenylyl cyclase can be mediated through the ubiquitous GTP-binding protein G_S subunit or through the olfactory isoform, G_olf, which predominates in the striatum. In this study, using double in situ hybridization, we show that virtually all striatal efferent neurons, identified by the expression of preproenkephalin A, substance P, or D₁ receptor mRNA, contained high amounts of G_olf mRNA and undetectable levels of G_s mRNA. In contrast, the large cholinergic interneurons contained both G_olf and G_s transcripts. To assess the functional relationship between dopamine or adenosine receptors and G-proteins, we examined G-protein levels in the striatum of D₁ and A_2A receptor knock-out mice. A selective increase in G_olf protein was observed in these animals, without change in mRNA levels. Conversely, G_olf levels were decreased in animals lacking a functional dopamine transporter. These results indicate that G_olf protein levels are regulated through D₁ and A_2A receptor usage. To determine the functional consequences of changes in G_olf levels, we used heterozygous G_olf knock-out mice, which possess half of the normal G_olf levels. In these animals, the locomotor effects of amphetamine and caffeine, two psychostimulant drugs that affect dopamine and adenosine signaling, respectively, were markedly reduced. Together, these results identify G_olf as a critical and regulated component of both dopamine and adenosine signaling.

Key words: Golf; Gs; G-protein; D₁ receptor; A_2A receptor; knock-out mice; striatum; dopamine; adenosine; dopamine transporter; homologous recombination

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21124390-10$05.00/0

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