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

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Abstract
In the striatum, dopamine D1and adenosine A2Areceptors 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 GαSsubunit or through the olfactory isoform, Gαolf, which predominates in the striatum. In this study, using doublein situhybridization, we show that virtually all striatal efferent neurons, identified by the expression of preproenkephalin A, substance P, or D1receptor mRNA, contained high amounts of GαolfmRNA and undetectable levels of GαsmRNA. In contrast, the large cholinergic interneurons contained both Gαolfand Gαstranscripts. To assess the functional relationship between dopamine or adenosine receptors and G-proteins, we examined G-protein levels in the striatum of D1and A2Areceptor knock-out mice. A selective increase in Gαolfprotein was observed in these animals, without change in mRNA levels. Conversely, Gαolflevels were decreased in animals lacking a functional dopamine transporter. These results indicate that Gαolfprotein levels are regulated through D1and A2Areceptor usage. To determine the functional consequences of changes in Gαolflevels, we used heterozygous Gαolfknock-out mice, which possess half of the normal Gαolflevels. 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 Gαolfas a critical and regulated component of both dopamine and adenosine signaling.