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Modeling bipolar disorder in mice by increasing acetylcholine or dopamine: chronic lithium treats most, but not all features

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Abstract

Rationale

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.

Objectives

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.

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Acknowledgments

We thank Drs. Berend Olivier, William Perry, and Arpi Minassian for their support. These studies were supported by NIH grants R01-MH071916, and R01-MH104344, as well as by the U.S. Veteran’s Administration VISN 22 Mental Illness Research, Education, and Clinical Center.

Conflict of interest

Dr. van Enkhuizen and Ms. Milienne-Petiot report no conflict of interest. Dr. Geyer has received consulting compensation from Abbott, Dart, Lundbeck, Neurocrine, Omeros, Otsuka, and Sunovion, and holds an equity interest in San Diego Instruments. Dr. Geyer also has research grant support from Intracellular Therapeutics, Johnson & Johnson, NIDA, NIMH, and the U.S. Veteran’s Administration VISN 22 Mental Illness Research, Education, and Clinical Center. Dr. Young has received consulting compensation from Amgen and Arena Pharmaceuticals as well as research grant support from Cerca, Omeros, Lundbeck Ltd, NIMH, and the U.S. Veteran’s Administration VISN 22 Mental Illness Research, Education, and Clinical Center. The aforementioned support did not direct any research presented here.

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Authors and Affiliations

  1. Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA

    Jordy van Enkhuizen, Morgane Milienne-Petiot, Mark A. Geyer & Jared W. Young

  2. Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584, CG, Utrecht, The Netherlands

    Jordy van Enkhuizen & Morgane Milienne-Petiot

  3. Research Service, VA San Diego Healthcare System, San Diego, CA, USA

    Mark A. Geyer & Jared W. Young

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  1. Jordy van Enkhuizen
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Correspondence to Jared W. Young.

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van Enkhuizen, J., Milienne-Petiot, M., Geyer, M.A. et al. Modeling bipolar disorder in mice by increasing acetylcholine or dopamine: chronic lithium treats most, but not all features. Psychopharmacology 232, 3455–3467 (2015). https://doi.org/10.1007/s00213-015-4000-4

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