Grant: Operating Grant

Most antipsychotic drugs use for the treatment of schizophrenia share the ability to block dopamine D2 receptor (D2R). These receptors have been shown to exert their action by activating G proteins. In addition to this mechanism, we have previously shown that D2R regulate the activity of the protein kinases Akt and GSK3 by acting trough a mechanism that involves the molecular scaffold beta arrestin 2 and the phosphatase PP2A. We have previously shown that the mood stabilizer drug lithium inhibits this second modality of D2R signaling. Recent evidence from our ongoing research program have uncovered a similar effect of the voltage gated sodium channel (Nav) blockers used to treat bipolar disorder on beta arrestin 2 mediated D2R signaling. Further examination of this effect has led to the identification of Nav1.6 as a new D2R interaction partner. Our results indicate that Nav1.6 changes D2R signaling from G protein mediated to beta arrestin mediated mechanisms. Here we propose to validate this signaling pathway as a target for the development of new psychoactive drugs. In a first research aim we will further characterize the interaction of D2R with Nav1.6. In a second aim we will validate the impact of disrupting the D2R/Nav1.6 interaction on behavior and brain physiology. In a last aim we will identify new compounds that can specifically block beta-arrestin mediated D2R signaling. Results obtain within this project will lay the path for the rational discovery of new mood stabilizers.