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Olanzapine causes a leptin-dependent increase in acetylcholine release in mouse prefrontal cortex
Asheley B Wathen1, Emily S West, Ralph Lydic
1Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA.
Sleep
|March 2, 2012
Summary
Olanzapine
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Olanzapine, an atypical antipsychotic, treats schizophrenia and bipolar disorder but has side effects like EEG slowing and increased leptin.
- The mechanisms of olanzapine's effects and its interaction with leptin are not fully understood.
- Acetylcholine (ACh) in the prefrontal cortex modulates sleep and wakefulness, and leptin influences cholinergic transmission.
Purpose of the Study:
- To investigate the hypothesis that olanzapine interacts with leptin to regulate ACh release in the prefrontal cortex.
- To explore the role of leptin in mediating olanzapine's effects on cholinergic neurotransmission.
Main Methods:
- Adult male C57BL/6J mice (n=33) and leptin-deficient mice (n=31) were used.
- Olanzapine was administered to the prefrontal cortex via microdialysis.
- Leptin replacement was achieved using subcutaneous micro-osmotic pumps in deficient mice.
Main Results:
- Olanzapine increased ACh release in both mouse groups, being significantly more potent in leptin-deficient mice.
- Olanzapine dissociated the normal coupling between increased cortical ACh release, arousal, and EEG activation.
- Leptin replacement restored and enhanced the olanzapine-induced increase in ACh release by 75%.
Conclusions:
- Systemic leptin replacement normalized the olanzapine-induced enhancement of ACh release in leptin-deficient mice.
- This suggests a crucial role for leptin in mediating olanzapine's effects on prefrontal cortex cholinergic activity.
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