Absence of the GPR37/PAEL receptor impairs striatal Akt and ERK2 phosphorylation, Delta FosB expression, and conditioned place preference to amphetamine and cocaine

The orphan G-protein-coupled receptor 37 (GPR37) colocalizes with the dopamine (DA) transporter (DAT) in mouse nigrostriatal presynaptic membranes, and its genetic ablation in homozygous null-mutant (GPR37-KO) mice provokes the marked increase of plasma membrane expression of DAT, alteration of psychostimulant-induced locomotor activity, and reduction of catalepsy induced by DA-receptor antagonists. We report that extracts from GPR37-KO mice displayed biochemical alterations of the nigrostriatal signaling pathways mediated by D1 and D2 dopaminergic receptors. Null-mutant mice showed an increase of the basal phosphorylation level of the D2-regulated Akt kinase. The basal phosphorylation of the D1-activated ERK2 kinase was not altered, but acute treatments with amphetamine or cocaine failed to produce its specific increase, as detected in samples from wild-type littermates. Furthermore, the chronic administration of cocaine to GPR37-KO mice did not increase the expression of the Delta FosB transcription factor isoforms. Consistently, behavioral analysis showed that null-mutant animals did not respond to the incentive properties of amphetamine or cocaine, in conditioned place preference tests. Thus, the lack of GPR37 affects both ERK2- and Akt-mediated striatal signaling pathways, impairing the biochemical and behavioral responses typically induced by acute and chronic administration of psychostimulant drugs.-Marazziti, D., Di Pietro, C., Mandillo, S., Golini, E., Matteoni, R., and Tocchini-Valentini, G. P. Absence of the GPR37/PAEL receptor impairs striatal Akt and ERK2 phosphorylation, Delta FosB expression, and conditioned place preference to amphetamine and cocaine. FASEB J. 25, 2071-2081 (2011). www.fasebj.org