Implication of dorsostriatal D3 receptors in motivational processes: a potential target for neuropsychiatric symptoms in Parkinson’s disease

Beyond classical motor symptoms, motivational and affective deficits are frequently observed in Parkinson’s disease (PD), dramatically impairing the quality of life of patients. Using bilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) in rats, we have been able to reproduce these neuropsychiatric/non-motor impairments. The present study describes how bilateral 6-OHDA SNc lesions affect the function of the main striatal dopaminergic (DA) receptor subtypes. Autoradiography was used to measure the levels of striatal DA receptors, and operant sucrose self-administration and neuropharmacological approaches were combined to investigate the causal implication of specific DA receptors subtypes in the motivational deficits induced by a dorsostriatal DA denervation. We found that D3 receptors (D(3)R) exclusively are down-regulated within the dorsal striatum of lesioned rats. We next showed that infusion of a D(3)R antagonist (SB-277011A) in non-lesioned animals specifically disrupts preparatory, but not consummatory behaviors. Our findings reveal an unexpected involvement of dorsostriatal D(3)R in motivational processes. They strongly suggest an implication of dorsostriatal D(3)R in the neuropsychiatric symptoms observed in PD, highlighting this receptor as a potential target for pharmacological treatment.