Bipolar disorder is characterized by sleep dysregulation, suggesting a role for the reticular activating system (RAS). Postmortem studies showed increased expression of neuronal calcium sensor protein 1 (NCS-1) in the brains of some bipolar disorder patients, and reduced or aberrant gamma band activity is present in the same disorder. Lithium (Li+) has been shown to effectively treat the mood disturbances in bipolar disorder patients. We previously showed that NCS-1 at low levels increased, and at high levels decreased, gamma oscillations in RAS pedunculopontine neurons (PPN), and that Li+ decreased these oscillations. We previously described the effects of each agent on oscillations, G-protein mechanisms, and Ca2+ currents. However, we designed the present experiments to determine the nature of the interaction of NCS-1 and Li+ at physiological concentrations that would have an effect within minutes of application. As expected, Li+ decreased gamma oscillation amplitude, while NCS-1 increased the amplitude of gamma oscillations. We identified NCS-1 at 2 mol/L as a concentration that increased gamma oscillations within 5-10 min, and Li+ at 10 mol/L as a concentration that decreased gamma oscillations within 5 min. The combined application of NCS-1 and Li+ at these concentrations showed that Li+ reduced the effects of NCS-1 on oscillation amplitude within 5-10 min. These results demonstrate that at physiological levels, Li+ acts to reduce the effects of NCS-1 so that, given over expression of NCS-1, Li+ would have salutary effects.