title: Modeling bipolar disorder in mice by increasing acetylcholine or dopamine: chronic lithium treats most, but not all features.
abstract: BACKGROUND
  Bipolar disorder (BD) is a disabling and life-threatening disease characterized by states of depression and mania. New and efficacious treatments have not been forthcoming partly due to a lack of well-validated models representing both facets of BD.
  
  
  OBJECTIVE
  We hypothesized that cholinergic- and dopaminergic-pharmacological manipulations would model depression and mania respectively, each attenuated by lithium treatment.
  
  
  METHODS
  C57BL/6 J mice received the acetylcholinesterase inhibitor physostigmine or saline before testing for "behavioral despair" (immobility) in the tail suspension test (TST) and forced swim test (FST). Physostigmine effects on exploration and sensorimotor gating were assessed using the cross-species behavioral pattern monitor (BPM) and prepulse inhibition (PPI) paradigms. Other C57BL/6 J mice received chronic lithium drinking water (300, 600, or 1200 mg/l) before assessing their effects alone in the BPM or with physostigmine on FST performance. Another group was tested with acute GBR12909 (dopamine transporter inhibitor) and chronic lithium (1000 mg/l) in the BPM.
  
  
  RESULTS
  Physostigmine (0.03 mg/kg) increased immobility in the TST and FST without affecting activity, exploration, or PPI. Lithium (600 mg/l) resulted in low therapeutic serum concentrations and normalized the physostigmine-increased immobility in the FST. GBR12909 induced mania-like behavior in the BPM of which hyper-exploration was attenuated, though not reversed, after chronic lithium (1000 mg/ml).
  
  
  CONCLUSIONS
  Increased cholinergic levels induced depression-like behavior and hyperdopaminergia induced mania-like behavior in mice, while chronic lithium treated some, but not all, facets of these effects. These data support a cholinergic-monoaminergic mechanism for modeling BD aspects and provide a way to assess novel therapeutics.
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA.
authors.forename: Jordy
authors.initials: J
authors.lastname: van Enkhuizen
authors.forename: Morgane
authors.initials: M
authors.lastname: Milienne-Petiot
authors.forename: Mark A
authors.initials: MA
authors.lastname: Geyer
authors.forename: Jared W
authors.initials: JW
authors.lastname: Young
mesh_terms: D000109:Acetylcholine; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001714:Bipolar Disorder; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003863:Depression; D004195:Disease Models, Animal; D004298:Dopamine; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D019417:Hindlimb Suspension; D018020:Lithium Compounds / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010830:Physostigmine / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D065808:Prepulse Inhibition / Q000187:drug effects; D055139:Sensory Gating / Q000187:drug effects; D013550:Swimming
chemical_list: D018692:Antimanic Agents; D002800:Cholinesterase Inhibitors; D018765:Dopamine Uptake Inhibitors; D018020:Lithium Compounds; D010879:Piperazines; C043425:vanoxerine; D010830:Physostigmine; D000109:Acetylcholine; D004298:Dopamine