Olanzapine causes a leptin-dependent increase in acetylcholine release in mouse prefrontal cortex

Abstract

Study Objectives: The atypical antipsychotic olanzapine is used effectively for treating symptoms of schizophrenia and bipolar disorder. Unwanted effects of olanzapine include slowing of the electroencephalogram (EEG) during wakefulness and increased circulating levels of leptin. The mechanisms underlying the desired and undesired effects of olanzapine are poorly understood. Sleep and wakefulness are modulated by acetylcholine (AC h) in the prefrontal cortex, and leptin alters cholinergic transmission. This study tested the hypothesis that olanzapine interacts with leptin to regulate AC h release in the prefrontal cortex. Design: Within/between subjects. Setting: University of Michigan. Patients or Participants: Adult male C57BL/6J (B6) mice (n = 33) and B6.V-Lep ob (leptin-deficient) mice (n = 31). Interventions: Olanzapine was delivered to the prefrontal cortex by microdialysis. Leptin-replacement in leptin-deficient mice was achieved using subcutaneous micro-osmotic pumps. Measurements and Results: Olanzapine caused a concentration-dependent increase in AC h release in B6 and leptin-deficient mice. Olanzapine was 230-fold more potent in leptin-deficient than in B6 mice for increasing AC h release, yet olanzapine caused a 51% greater AC h increase in B6 than in leptin-deficient mice. Olanzapine had no effect on recovery time from general anesthesia. Olanzapine increased EEG power in the delta (0.5-4 Hz) range. Thus, olanzapine dissociated the normal coupling between increased cortical AC h release, increased behavioral arousal, and EEG activation. Leptin replacement significantly enhanced (75%) the olanzapine-induced increase in AC h release. Conclusion: Replacing leptin by systemic administration restored the olanzapine-induced enhancement of AC h release in the prefrontal cortex of leptin-deficient mouse.