Receptor density influences the recruitment bias of aripiprazole and brexpiprazole at the dopamine D_2L receptor

AbstractAripiprazole, brexpiprazole, and cariprazine are dopamine D2 receptor ligands considered as effective and tolerable antipsychotics. Brain imaging studies showed that schizophrenia is characterized by elevated dopamine receptor density, which is exacerbated by antipsychotic treatments. Despite the complexity of translating in vitro studies to human neurobiology, overexpression experiments in transfected cells provide a proof‐of‐concept model of the influence of receptor density on antipsychotic treatments. Since receptor density was demonstrated to influence the signaling profile of dopaminergic ligands, we hypothesized that high dopamine D2 receptor expression levels could influence the recruitment of Gi1 and β‐arrestin2 in response to partial agonists used as antipsychotics. A nanoluciferase complementation assay was used to monitor β‐arrestin2 and Gi1 recruitment at the dopamine D2L receptor in response to aripiprazole, brexpiprazole, and cariprazine. This was performed in transfected cells carrying a doxycycline‐inducible system allowing to manipulate the expression of the dopamine D2L receptors. Increasing D2L receptor density reoriented aripiprazole's preferential recruitment from Gi1 to β‐arrestin2. With respect to brexpiprazole, which showed inverse agonism for β‐arrestin2 recruitment at the lower receptor density tested, inverse agonism for Gi1 recruitment was observed when tested at a high receptor expression level. At variance, cariprazine evoked a potent partial agonism for β‐arrestin2 recruitment only, in all the tested conditions. D2L receptor density appears to shape the recruitment bias of aripiprazole and brexpiprazole, but not cariprazine. This suggests that changes in receptor expression level could qualitatively influence the functional response of partial agonists used in psychiatry.