GPR143, an L-DOPA receptor, in cholinergic interneurons, modulates haloperidol-induced extrapyramidal symptoms through coupling between GPR143 and dopamine D2 receptor

Abstract

We propose that L-DOPA by itself is a neurotransmitter. Recently, GPR143 was identified as an L-DOPA receptor. We previously showed non-effective dose of L-DOPA potentiates behavioral response to quinpirole, a dopamine D2 receptor (D2R) agonist. However, it remains undetermined whether and how GPR143 regulates D2R-mediated behaviors. 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 compared to wild-type (WT) mice. To clarify which neural circuits that are responsible for this phenotype, we investigated haloperidol-induced catalepsy using conditional KO mice that expressing cre recombinase in D2R-, adenosine A2A receptor (indirect pathway)-, and in choline acetyltransferase (cholinergic interneuron)-positive neurons. Haloperidol-induced catalepsy was attenuated in D2R-cre (+); Gpr143^flox/y and ChAT-cre; Gpr143^flox/y mice. Furthermore, we found that a synthetic peptide, which inhibited the interaction between GPR143 and D2R, attenuated haloperidol-induced catalepsy. These results suggest that GPR143 expressed in the striatal cholinergic interneurons modulates haloperidol-induced extrapyramidal symptoms through coupling GPR143 and D2R.