G-protein coupled receptor 6 deficiency alters striatal dopamine and cAMP concentrations and reduces dyskinesia in a mouse model of Parkinson's disease

• Gpr6 deficiency leads to a reduction of striatal cAMP and an increase of dopamine.
• P-DARPP-32 concentrations are increased in the striatum of Gpr6 deficient mice.
• Gpr6 deficient mice show higher basal locomotor activity.
• Higher basal locomotor activity persists after haloperidol treatment.
• Gpr6 deficiency reduces dyskinesia in a mouse model of Parkinson's disease.

The orphan G-protein coupled receptor 6 (GPR6) is a constitutively active receptor which is positively coupled to the formation of cyclic adenosine-3′,5′-monophosphate (cAMP). GPR6 is predominantly expressed in striatopallidal neurons. Here, we investigated neurochemical and behavioural effects of Gpr6 deficiency in mice.Gpr6 depletion decreased in vivo cAMP tissue concentrations (20%) in the striatum. An increase of striatal tissue dopamine concentrations (10%) was found in Gpr6−/− mice, whereas basal extracellular dopamine levels were not changed compared with Gpr6+/+ mice, as shown by in vivo microdialysis. Western blot analyses revealed no alteration in the expression and subcellular localisation of the dopamine D2 receptor in the striatum of Gpr6−/− mice, and the number of tyrosine hydroxylase positive neurons in the substantia nigra was unchanged. DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) expression in the striatum of Gpr6−/− mice was not altered, however, a twofold increase in the phosphorylation of DARPP-32 at Thr34 was detected in Gpr6−/− compared with Gpr6+/+ mice. Gpr6−/− mice showed higher locomotor activity in the open field, which persisted after treatment with the dopamine D2 receptor antagonist haloperidol. They also displayed reduced abnormal involuntary movements after apomorphine and quinpirole treatment in the mouse dyskinesia model of Parkinson's disease.In conclusion, the depletion of Gpr6 reduces cAMP concentrations in the striatum and alters the striatal dopaminergic system. Gpr6 deficiency causes an interesting behavioural phenotype in the form of enhanced motor activity combined with reduced abnormal involuntary movements. These findings could offer an opportunity for the treatment of Parkinson's disease beyond dopamine replacement.