G-protein coupled receptor 88 knock-down in the associative striatum reduces the psychiatric symptoms in a translational model of Parkinson’s disease

Beyond the motor disability, Parkinson’s disease (PD) is also characterized by an early appearance of psychiatric symptoms such as apathy, depression, anxiety and cognitive deficits, which can entail dementia and psychosis in later stages. While current treatments may provide some level of symptomatic relief, their use is limited by the development of adverse effects such as impulse-control disorders. There is thus a medical need for targets with novel modes of action to treat these aspects of PD. In this context, we investigated GPR88, an orphan G-protein coupled receptor that is associated with psychiatric disorders and highly enriched in the striatum, where it exerts an inhibitory control over neurotransmitter systems that are compromised in PD. To evaluate the potential of GPR88 as a target for the treatment of the psychiatric symptoms of PD, we knocked-down (KD) its expression in sensorimotor (dorsolateral, DLS) or associative (dorsomedial, DMS) striatal areas in a translational rat model of early PD. Our findings indicate that Gpr88- KD in the DMS, but not DLS, reduced the alterations in mood, motivation and cognition that characterized the model, through modulation of the expression of regulator of G-protein signaling 4 ( Rgs4 ) and of transcription factor ΔFosB. Furthermore, the rat model of PD exhibited allostatic changes in striatal activity markers that may be related to patterns observed in patients, and which were reduced by Gpr88- KD. Taken together, these results thus highlight the relevance of GPR88 as a therapeutic target for the psychiatric symptoms of PD.