The mania-like exploratory profile in genetic dopamine transporter mouse models is diminished in a familiar environment and reinstated by subthreshold psychostimulant administration
Introduction
Bipolar Disorder (BD) is a major and debilitating psychiatric disorder, affecting approximately 1–2% of the population. The heritability of BD has been estimated between 50 and 80%, suggesting a strong genetic component to the disorder. Despite treatment availability for BD, prognosis remains poor with 15% committing suicide. While some treatments were discovered serendipitously through chance observations, such as lithium (Gould and Einat, 2007), others were originally designed for other psychiatric disorders, such as antipsychotic treatment for schizophrenia. Thus, individuals with BD have not benefited from a treatment strategy that was designed specifically to treat the pathology of the disorder, possibly contributing to poor prognosis (Einat, 2006).
One rate-limiting step in developing treatments for BD has been the lack of suitable animal models (Gould and Einat, 2007). While some models exist, they are not necessarily derived from the limited understanding we possess about the neuropathology of BD. For example, amphetamine administration was first used as a model of mania based upon the observed behavior of rats after administration, not as an a priori hypothesis on the neurobiological underpinnings of the disorder (Davies et al., 1974, Randrup and Munkvad, 1974, Rushton and Steinberg, 1963). This lack of etiological validity may limit the development of novel therapeutics for treating BD, thus explaining why current treatments were only serendipitously discovered or adopted from other psychiatric conditions (Gould and Einat, 2007).
A model of BD mania we have proposed is based on the putative reduced functioning of the dopamine transporter (DAT) in BD patients. Genetic linkage studies have linked the DAT and BD (Greenwood et al., 2001, Greenwood et al., 2006, Kelsoe et al., 1996), with lower levels of the DAT being reported in BD (Amsterdam and Newberg, 2007). Moreover, reduced expression of DAT has been observed in BD patients (Horschitz et al., 2005). We observed that mice with reduced functioning DAT levels (via genetic or pharmacological manipulation), exhibit a phenotype in the mouse Behavioral Pattern Monitor (BPM) that is consistent with that of acutely manic BD patients in a human BPM, specifically increased activity, increased specific exploration, and reduced spatial d (Perry et al., 2009, Young et al., 2010, Young et al., 2007).
Mania is the cardinal feature of BD, as exemplified by the fact that it is a core symptom in the diagnosis of both Type I and Type II BD according to the DSM IV. Other behavioral abnormalities exist in BD however, with patients classically alternating between episodes of mania and depression. Between these episodes patients are typically in a euthymic state characterized by relative behavioral stability with little to no hyperactive or manic behaviors. Very few animal models of BD attempt to mimic the full spectrum of the disorder. The kindling and intermittent cocaine (Post, 2007) models attempt to model cycling effects in rodents, but fall short of modeling specific behavioral phenotypes exhibited by BD patients (Young and Geyer, 2010).
The genetic and pharmacological DAT models we presented previously appear to mimic the symptoms of the manic phase of BD (Perry et al., 2009, Young et al., 2010). These models include DAT knockdown (KD) mice, which exhibit chronic low level expression (10%) of the DAT (Zhuang et al., 2001) and selective inhibition of the DAT with GBR 12909 (Heikkila and Manzino, 1984). Mice from each model exhibited hyperactivity and increased specific exploration, as well as greater straight line movements represented by the fractal geometry measure spatial d. This behavioral profile was consistent with the abnormal exploratory behavior of manic BD patients (Perry et al., 2009). These models may therefore prove useful in the development of treatments specifically targeted for the treatment of BD mania. To prove useful as a drug discovery model in which animal use is maximized however, it would be beneficial to know whether the mania-like exploratory profile of these models is observed following subsequent exposures to the testing environment. Thus, in the present studies, we investigated the exploratory behavioral profile of these models following initial familiarization to the BPM testing environment. Specifically, we examined whether the mania-like behavioral profiles observed in these BD models would still be observed with repeated testing.
Section snippets
Animals
DAT KD mice were generated by inserting altered embryonic stem cells of the 129 Sv/J mouse strain in C57BL/6J blastocysts. These stem cells were altered as detailed by Zhuang et al (2001). In brief, a 7.5-kb HindIII fragment containing the first two exons of the DAT gene was excised from a phage DNA isolated from a mouse 129 Sv/J genomic library. A Not1 and Asc1 cassette was inserted to generate the targeting construct. This cassette contained the tetracycline-dependent transactivator tTA, the
Experiment 1: Exploratory profile of DAT mutant mice in a familiar BPM environment (previously exposed to the BPM two weeks prior to testing)
DAT KD and WT mice were reassessed in the mBPM two weeks after initial exposure to determine whether the mania-like phenotype of these mice was consistent with repeated testing.
Discussion
In the present studies, we performed a longitudinal assessment of the exploratory behavior of our pharmacological and genetic mouse models of BD mania. We previously reported that DAT KD mice and mice administered GBR 12909 exhibit an exploratory profile in the mouse BPM consistent with that of patients with bipolar mania assessed in the human BPM, specifically increased activity and specific exploration, as well as reduced spatial d (Perry et al., 2009, Young et al., 2010). The present studies
Acknowledgements
We thank Richard Sharp, Virginia Masten, and Mahálah Buell for their support. This study was supported by NIH grants R01-DA02925, R21-MH085221, and R01-MH071916, as well as by a NARSAD Young Investigators Award (JWY) and by the Veteran's Administration VISN 22 Mental Illness Research, Education, and Clinical Center.
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