Involvement of GPR143, an L-DOPA receptor, in haloperidol-induced extrapyramidal symptoms

We propose that L-DOPA by itself is a neurotransmitter. Recently, a G-protein-related receptor (GPCR) GPR143, a gene product of ocular-albinism1, was identified as an L-DOPA receptor. We previously showed that non-effective dose of L-DOPA potentiates behavioral response to quinpirole, a dopamine D2 receptor (D2R). However, it remains undetermined whether and how GPR143 regulates D2R-mediated behaviors. In this study, we analyzed behavioral responses to several D2R ligands using Gpr143 gene-deficient (GPR143-KO) mice. We found that haloperidol, a D2R antagonist (0.5mg/kg)-induced catalepsy was attenuated in GPR143-KO mice when compared to wild type (WT) mice. To clarify which neuron circuits are responsible for this phenotype, we investigated haloperidol-induced catalepsy using mice that expressing cre recombinase in D2R-, adenosine A2a receptor (indirect pathway)-, choline acetyltransferase (cholinergic interneuron)-positive neurons. Haloperidol-induced catalepsy was attenuated in D2R-cre (+); Gpr143flox/y and ChAT-cre; Gpr143flox/y mice. These results suggest that GPR143 expressed in the striatal cholinergic interneurons plays an important role in haloperidol-induced catalepsy.