GPR88, an orphan G protein-coupled receptor, was designated Strg/GPR88 for striatum-specific G protein-coupled receptor (K. Mizushima et al. (2000)Genomics, 69, 314-321). In this study, we focused on striatal GPR88 protein localization using a polyclonal antibody. We established that the distribution of immunoreactivity in rat brain matched that of GPR88 transcripts and provided evidence for its exclusive neuronal expression. GPR88 protein is abundant throughout the striatum of rat and primate, with expression limited to the two subsets of striatal projection medium spiny neurons (MSNs) expressing preprotachykinin-substance P or preproenkephalin mRNAs. Ultrastructural immunolabelling revealed the GPR88 concentration at post-synaptic sites along the somatodendritic compartments of MSNs, with pronounced preference for dendrites and dendritic spines. The GPR88-rich expression, in both striatal output pathways, designates this receptor as a potential therapeutic target for diseases involving dysfunction of the basal ganglia, such as Parkinson's disease. Hence, we investigated changes of GPR88 expression in a model of Parkinson's disease (unilateral 6-hydroxydopamine-lesioned rats) following repeated L-DOPA treatment. In dopamine-depleted striatum, GPR88 expression was differentially regulated, i.e. decreased in striatopallidal and increased in striatonigral MSNs. L-DOPA treatment led to a normalization of GPR88 levels through dopamine D1 and D2 receptor-mediated mechanisms in striatopallidal and striatonigral MSNs, respectively. Moreover, the removal of corticostriatal inputs, by ibotenate infusion, downregulated GPR88 in striatopallidal MSNs. These findings provide the first evidence that GPR88 is confined to striatal MSNs and indicate that L-DOPA-mediated behavioural effects in hemiparkinsonian rats may involve normalization of striatal GPR88 levels probably through dopamine receptor-mediated mechanisms and modulations of corticostriatal pathway activity.