title: Dopamine depletion attenuates some behavioral abnormalities in a hyperdopaminergic mouse model of bipolar disorder.
abstract: BACKGROUND
  Patients with BD suffer from multifaceted symptoms, including hyperactive and psychomotor agitated behaviors. Previously, we quantified hyperactivity, increased exploration, and straighter movements of patients with BD mania in the human Behavioral Pattern Monitor (BPM). A similar BPM profile is observed in mice that are hyperdopaminergic due to reduced dopamine transporter (DAT) functioning. We hypothesized that dopamine depletion through alpha-methyl-p-tyrosine (AMPT) administration would attenuate this mania-like profile.
  
  
  METHODS
  Male and female DAT wild-type (WT; n=26) and knockdown (KD; n=28) mice on a C57BL/6 background were repeatedly tested in the BPM to assess profile robustness and stability. The optimal AMPT dose was identified by treating male C57BL/6 mice (n=39) with vehicle or AMPT (10, 30, or 100mg/kg) at 24, 20, and 4h prior to testing in the BPM. Then, male and female DAT WT (n=40) and KD (n=37) mice were tested in the BPM after vehicle or AMPT (30mg/kg) treatment.
  
  
  RESULTS
  Compared to WT littermates, KD mice exhibited increased activity, exploration, straighter movement, and disorganized behavior. AMPT-treatment reduced hyperactivity and increased path organization, but potentiated specific exploration in KD mice without affecting WT mice.
  
  
  CONCLUSIONS
  AMPT is not specific to dopamine and also depletes norepinephrine.
  
  
  CONCLUSIONS
  KD mice exhibit abnormal exploration in the BPM similar to patients with BD mania. AMPT-induced dopamine depletion attenuated some, but potentiated other, aspects of this mania-like profile in mice. Future studies should extend these findings into other aspects of mania to determine the suitability of AMPT as a treatment for BD mania.
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, United States; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Jordy
authors.initials: J
authors.lastname: van Enkhuizen
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, United States; Research Service, VA San Diego Healthcare System, San Diego, CA, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Geyer
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, United States.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Halberstadt
authors.affiliation: Department of Neurobiology, University of Chicago, Chicago, IL, United States.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Zhuang
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, United States; Research Service, VA San Diego Healthcare System, San Diego, CA, United States. Electronic address: jaredyoung@ucsd.edu.
authors.forename: Jared W
authors.initials: JW
authors.lastname: Young
mesh_terms: D000818:Animals; D001714:Bipolar Disorder / Q000503:physiopathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000502:physiology; D005106:Exploratory Behavior / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019805:alpha-Methyltyrosine / Q000008:administration & dosage
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D019805:alpha-Methyltyrosine; D004298:Dopamine
keywords: AMPT; Bipolar disorder; Dopamine transporter; Mania; Mice