Mice with Deficiency of Gγ 7 in Dopamine D 1 Receptor Expressing Neurons Exhibit a Hypolocomotor Phenotype

In striatal neurons, dopamine stimulates adenylyl cyclase activity via a heterotrimeric G protein that contains Gα olf and Gγ 7 . Surprisingly, despite impairment of dopamine D 1 receptor stimulated adenylyl cyclase activity in the striatum, Gng7 −/− mice do not display a hypolocomotor phenotype. However, Gng7 −/− mice also show impaired adenosine A 2a receptor signaling in the striatum. To test the hypothesis that normal locomotor activity in Gng7 −/− mice results from a balanced deficit in these two signal transduction pathways, we created mice with deficiency of Gγ 7 specifically in dopamine D 1 receptor expressing neurons. Gng7 fl/fl ; Drd1a Cre/+ mice show reduced locomotion in a behavioral ethogram, reduced exploratory behavior in a novel environment, and a markedly reduced locomotor response to the indirect dopamine agonist amphetamine, but a normal locomotor response to a high dose of the adenosine A 2a receptor antagonist caffeine. These results affirm the importance of Gγ 7 in transducing signals from the dopamine D 1 receptor in the control of locomotor activity. In conjunction with the lack of a locomotor phenotype in Gng7 −/− mice, these results suggest that Gγ 7 coupled, adenosine A 2a receptor mediated signaling may be equally important in regulating locomotor behavior. Our results are consistent with recent studies that have demonstrated a potential role for adenosine A 2a antagonists in the treatment of Parkinson's Disease. Supported by NIH grant GM39867.