The mania-like exploratory profile in genetic dopamine transporter mouse models is diminished in a familiar environment and reinstated by subthreshold psychostimulant administration

Abstract

Bipolar Disorder (BD) is a neuropsychiatric disorder characterized by symptoms ranging from a hyperactive manic state to depression, with periods of relative stability, known as euthymia, in between. Although prognosis for BD sufferers remains poor, treatment development has been restricted due to a paucity of validated animal models. Moreover, most models focus on the manic state of BD with little done to characterize the longitudinal behavior of these models. We recently presented two dopamine transporter (DAT) mouse models of BD mania: genetic (DAT knockdown; KD, mice) and pharmacological (the selective DAT inhibitor GBR 12909). These models exhibit an exploratory profile consistent with the quantified exploratory profile of manic BD patients observed in the cross-species translational test, the Behavioral Pattern Monitor (BPM).

To further explore the suitability of these models, we examined the effects of reduced DAT function on the behavior of mice tested after familiarization to the BPM environment. Testing with 16 mg/kg GBR 12909 in familiarized mice resulted in a consistent mania-like profile. In contrast, the mania-like profile of DAT KD mice disappears in a familiar environment, with partial reinstatement elicited by the introduction of novelty. In addition, we found that a subthreshold dose of GBR 12909 (9 mg/kg) reinstated the mania-like profile in DAT KD mice without affecting wildtype behavior.

Thus, the mania-like exploratory profile of DAT KD mice is reduced in a familiar environment, partially reinstated with novelty, but is fully restored when administered a stimulant that is ineffective in wildtype mice. These mice may provide a model of BD from mania to euthymia and back again with stimulant treatment. Acute blockade of the DAT by GBR 12909 however, may provide a consistent model for BD mania.

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.