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In the striatum, dopamine D1 and adenosine A2A 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 GαS subunit or through the olfactory isoform, Gαolf, 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 Gαolf mRNA and undetectable levels of Gαs mRNA. In contrast, the large cholinergic interneurons contained both Gαolf and Gαstranscripts. To assess the functional relationship between dopamine or adenosine receptors and G-proteins, we examined G-protein levels in the striatum of D1 and A2A receptor knock-out mice. A selective increase in Gαolf protein was observed in these animals, without change in mRNA levels. Conversely, Gαolf levels were decreased in animals lacking a functional dopamine transporter. These results indicate that Gαolf protein levels are regulated through D1and A2A receptor usage. To determine the functional consequences of changes in Gαolf levels, we used heterozygous Gαolf knock-out mice, which possess half of the normal Gαolf 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 Gαolf as a critical and regulated component of both dopamine and adenosine signaling.

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

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