Enhanced effect of the hallucinogen DOI in L-DOPA receptor Gpr143-deficient mice

Hallucinogens, such as lysergic acid diethylamide, act primarily through the 5-hydroxytryptamine 2A (5-HT2A) receptor, but their regulatory mechanisms remain unclear. G protein-coupled receptor 143 (GPR143), an L-3,4-dihydroxyphenylalanine (L-DOPA) receptor, modulates specific GPCRs. We examined the role of GPR143 in the action of 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). DOI-induced hyperlocomotion and c-Fos expression in the nucleus accumbens were enhanced in GPR143 knockout mice. In Chinese hamster ovary cells expressing 5-HT2A receptor, DOI-induced extracellular signal-regulated kinase phosphorylation was suppressed by co-expression of GPR143. These findings suggest that GPR143 negatively regulates 5-HT2A receptor signaling and attenuates behavioral responses to hallucinogens.