Coexistence of D 3 R typical and atypical signaling in striatonigral neurons during dopaminergic denervation. Correlation with D 3 nf expression changes.

Dopamine D3R are widely expressed in basal ganglia where interact with D1R. D3R potentiate cAMP accumulation and GABA release stimulated by D1R in striatonigral neurons through "atypical" signaling. During dopaminergic denervation, D3R signaling changes to a "typical" in which antagonizes the effects of D1R, the mechanisms of this switching are unknown. D(3)nf splice variant regulates membrane anchorage and function of D3R and decreases in denervation; thus, it is possible that D3R signaling switching correlates with changes in D(3)nf expression and increases of membranal D3R that mask D3R atypical effects. We performed experiments in unilaterally 6-hydroxydopamine lesioned rats and found a decrease in mRNA and protein of D(3)nf, but not of D3R in the denervated striatum. Proximity ligation assay showed that D3R-D(3)nf interaction decreased after denervation, whereas binding revealed an increasedB(max)in D3R. The new D3R antagonized cAMP accumulation and GABA release stimulated by D1R; however, in the presence of N-Ethylmaleimide (NEM), to block G(i)protein signaling, activation of D3R produced its atypical signaling stimulating D1R effects. Finally, we investigated if the typical and atypical effects of D3R modulating GABA release are capable of influencing motor behavior. Injections of D3R agonist into denervated nigra decreased D1R agonist-induced turning behavior but potentiated it in the presence of NEM. Our data indicate the coexistence of D3R typical and atypical signaling in striatonigral neurons during denervation that correlated with changes in the ratio of expression of D(3)nf and D3R isoforms. The coexistence of both atypical and typical signaling during denervation influences motor behavior.