title: Olanzapine causes a leptin-dependent increase in acetylcholine release in mouse prefrontal cortex.
abstract: OBJECTIVE
  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 (ACh) in the prefrontal cortex, and leptin alters cholinergic transmission. This study tested the hypothesis that olanzapine interacts with leptin to regulate ACh release in the prefrontal cortex.
  
  
  METHODS
  Within/between subjects.
  
  
  METHODS
  University of Michigan.
  
  
  METHODS
  Adult male C57BL/6J (B6) mice (n = 33) and B6.V-Lep(ob) (leptin-deficient) mice (n = 31).
  
  
  METHODS
  Olanzapine was delivered to the prefrontal cortex by microdialysis. Leptin-replacement in leptin-deficient mice was achieved using subcutaneous micro-osmotic pumps.
  
  
  RESULTS
  Olanzapine caused a concentration-dependent increase in ACh release in B6 and leptin-deficient mice. Olanzapine was 230-fold more potent in leptin-deficient than in B6 mice for increasing ACh release, yet olanzapine caused a 51% greater ACh 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 ACh release, increased behavioral arousal, and EEG activation. Leptin replacement significantly enhanced (75%) the olanzapine-induced increase in ACh release.
  
  
  CONCLUSIONS
  Replacing leptin by systemic administration restored the olanzapine-induced enhancement of ACh release in the prefrontal cortex of leptin-deficient mouse.
authors.affiliation: Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Asheley B
authors.initials: AB
authors.lastname: Wathen
authors.forename: Emily S
authors.initials: ES
authors.lastname: West
authors.forename: Ralph
authors.initials: R
authors.lastname: Lydic
authors.forename: Helen A
authors.initials: HA
authors.lastname: Baghdoyan
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D004569:Electroencephalography; D020738:Leptin / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000077152:Olanzapine; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D014851:Wakefulness / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D020738:Leptin; D001569:Benzodiazepines; D000077152:Olanzapine; D000109:Acetylcholine