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The effects of reduced dopamine transporter function and chronic lithium on motivation, probabilistic learning, and neurochemistry in mice: Modeling bipolar mania.
- Source :
-
Neuropharmacology [Neuropharmacology] 2017 Feb; Vol. 113 (Pt A), pp. 260-270. Date of Electronic Publication: 2016 Oct 11. - Publication Year :
- 2017
-
Abstract
- Background: Bipolar disorder (BD) mania patients exhibit poor cognition and reward-seeking/hypermotivation, negatively impacting a patient's quality of life. Current treatments (e.g., lithium), do not treat such deficits. Treatment development has been limited due to a poor understanding of the neural mechanisms underlying these behaviors. Here, we investigated putative mechanisms underlying cognition and reward-seeking/motivational changes relevant to BD mania patients using two validated mouse models and neurochemical analyses.<br />Methods: The effects of reducing dopamine transporter (DAT) functioning via genetic (knockdown vs. wild-type littermates), or pharmacological (GBR12909- vs. vehicle-treated C57BL/6J mice) means were assessed in the probabilistic reversal learning task (PRLT), and progressive ratio breakpoint (PRB) test, during either water or chronic lithium treatment. These tasks quantify reward learning and effortful motivation, respectively. Neurochemistry was performed on brain samples of DAT mutants ± chronic lithium using high performance liquid chromatography.<br />Results: Reduced DAT functioning increased reversals in the PRLT, an effect partially attenuated by chronic lithium. Chronic lithium alone slowed PRLT acquisition. Reduced DAT functioning increased motivation (PRB), an effect attenuated by lithium in GBR12909-treated mice. Neurochemical analyses revealed that DAT knockdown mice exhibited elevated homovanillic acid levels, but that lithium had no effect on these elevated levels.<br />Conclusions: Reducing DAT functioning recreates many aspects of BD mania including hypermotivation and improved reversal learning (switching), as well as elevated homovanillic acid levels. Chronic lithium only exerted main effects, impairing learning and elevating norepinephrine and serotonin levels of mice, not specifically treating the underlying mechanisms identified in these models.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Bipolar Disorder psychology
Brain Chemistry drug effects
Conditioning, Operant drug effects
Conditioning, Operant physiology
Disease Models, Animal
Drug Administration Schedule
Homovanillic Acid metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Motivation drug effects
Problem Solving drug effects
Bipolar Disorder metabolism
Brain Chemistry physiology
Dopamine Plasma Membrane Transport Proteins physiology
Lithium administration & dosage
Motivation physiology
Problem Solving physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-7064
- Volume :
- 113
- Issue :
- Pt A
- Database :
- MEDLINE
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 27732870
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2016.07.030