Disruption of the l-DOPA Receptor Gpr143/OA1-Gene in Mice Creates a Unique Mixed Psychosis-Like Phenotype

GPR143, originally identified as the gene product of ocular albinism 1 (OA1), a G protein-coupled receptor (GPCR), can function as a receptor for l-3,4-dihydroxyphenylalanine (DOPA), a precursor of dopamine (DA). To examine the physiological and pathophysiological roles of GPR143, we analyzed the behavior of Gpr143 gene-deficient (Gpr143^-/y) mice. We performed comprehensive behavioral analyses including the prepulse inhibition test, sucrose preference test, light-dark exploration test, etc. and microarray analysis. Gpr143^-/y mice displayed a mixed psychosis-like phenotype: impaired prepulse inhibition (a characteristic of schizophrenia) combined with reward system aberrations, depression, and heightened aggression (characteristic of mood disorders). By microarray analysis, we identified 17 downregulated and 20 upregulated genes in the forebrain of Gpr143^-/y mice, genes putatively involved in serotonergic and/or dopaminergic transmission. These findings suggest that GPR143 plays a role in mesolimbic and mesocortical functions underlying sensory gating, reward, social hierarchy, cognition, and emotional regulation. These data further suggest both a new animal model and a unique therapeutic focus for a heretofore difficult to study and treat mixed psychosis-like condition.