The causes of bipolar disorder (BPD) are not well understood and the therapeutic approaches are limited. The actions of Li+ and other anti-psychotic agents (ApsA) on membrane receptors and channels are related J to the modulation of intra- and extracellular Ca 2+ levels. We have cloned a Ca2+-sensing receptor (CaR) that plays a key role in the regulation of Ca/+ homeostasis and found that new specific CAR potentiators,/ calcimimetics, elicit beneficial effects on neuronal excitability and neurotransmission. The CaR is homologous to glutamate receptors (GR) and is functionally linked to both metabotropic GR (mGluR) and NMDA-type GR that are dysfunctional in psychosis. Based on our preliminary studies we suggest that the CaR potentiators can be applied for correction of these disturbances in BPD. We will also evaluate their synergistic actions with other ApsA including Li+. Li+ may exert its beneficial effects on BPD by modulating signal transduction pathways in the brain that are also regulated by CaR. One of the common side effects of Li is hypercalcemia that can be treated by CaR potentiators. We also found that these agents inhibit channels which likely play a role in rapid cycling BPD and that they can prevent the actions of phencyclidine (PCP) and other psychotomimetic agents on neuronal functions, thus displaying the characteristics of potent ApsA. We, therefore, hypothesize that the CaR potentiators can be used in combination with Li+ and other ApsA for treating BPD and for preventing complications associated with the side effects of Li+. We will characterize their effects on neuronal functions and will pursue the following specific aims: 1) To determine the role of the CaR and CaR-regulated signaling pathways as targets of Li+ action and the modulation by CaR potentiators and Li+ of channels involved in rapid cycling BPD. 2) To evaluate the application of the CAR potentiators as activators of NMDA channels, opposing the actions of PCP and other agents used for generating experimental models of psychotic states. 3) To document that there are positive functional links between CaR and mGluR2 by showing that the CaR potentiators can act via mGluR2 to prevent overstimulation by psychotomimetic agents and characterize the synergistic actions of CaR potentiators and other antipsychotic agents. These studies should provide new insights into the pathogenesis and treatment of bipolar disorder. In the long term, the application of CaR potentiators and their synergistic actions with other antipsychotic drugs could help introducing novel therapeutic strategies.