G alpha(olf) levels are regulated by receptor usage and control dopamine and adenosine action in the striatum

In the striatum, dopamine D-1 and adenosine A(2A) receptors stimulate the p roduction of cAMP, which is involved in neuromodulation and long-lasting ch anges in gene expression and synaptic function. Positive coupling of recept ors to adenylyl cyclase can be mediated through the ubiquitous GTP-binding protein G alpha (S) subunit or through the olfactory isoform, G alpha (olf) , which predominates in the striatum. In this study, using double in situ h ybridization, we show that virtually all striatal efferent neurons, identif ied by the expression of preproenkephalin A, substance P, or D-1 receptor m RNA, contained high amounts of G alpha (olf) mRNA and undetectable levels o f G alpha (S) mRNA. In contrast, the large cholinergic interneurons contain ed both G alpha (olf) and G alpha (S) transcripts. To assess the functional relationship between dopamine or adenosine receptors and G- proteins, we e xamined G- protein levels in the striatum of D-1 and A(2A) receptor knockou t mice. A selective increase in G alpha (olf) protein was observed in these animals, without change in mRNA levels. Conversely, G alpha (olf) levels w ere decreased in animals lacking a functional dopamine transporter. These r esults indicate that G alpha (olf) protein levels are regulated through D-1 and A(2A) receptor usage. To determine the functional consequences of chan ges in G alpha (olf) levels, we used heterozygous G alpha (olf) knock-out m ice, which possess half of the normal G alpha (olf) levels. In these animal s, the locomotor effects of amphetamine and caffeine, two psychostimulant d rugs that affect dopamine and adenosine signaling, respectively, were marke dly reduced. Together, these results identify G alpha (olf) as a critical a nd regulated component of both dopamine and adnesine signaling.