Elsevier

Neuroscience

Volume 321, 3 May 2016, Pages 163-188
Neuroscience

Review
Animal models of bipolar mania: The past, present and future

https://doi.org/10.1016/j.neuroscience.2015.08.041Get rights and content

Highlights

  • Pharmacological approaches to induce hyperactivity as a model of human mania have been used for many years.

  • Environmental manipulations are used to induce manic-like states which mimic multiple facets of this complex disorder.

  • Most recent studies have focused on genetic models.

  • Certain outbred strains of mice may be useful in modeling the polygenic nature of this disease.

  • Ultimately, models that cycle through various mood states are needed.

Abstract

Bipolar disorder (BD) is the sixth leading cause of disability in the world according to the World Health Organization and affects nearly six million (∼2.5% of the population) adults in the United State alone each year. BD is primarily characterized by mood cycling of depressive (e.g., helplessness, reduced energy and activity, and anhedonia) and manic (e.g., increased energy and hyperactivity, reduced need for sleep, impulsivity, reduced anxiety and depression), episodes. The following review describes several animal models of bipolar mania with a focus on more recent findings using genetically modified mice, including several with the potential of investigating the mechanisms underlying ‘mood’ cycling (or behavioral switching in rodents). We discuss whether each of these models satisfy criteria of validity (i.e., face, predictive, and construct), while highlighting their strengths and limitations. Animal models are helping to address critical questions related to pathophysiology of bipolar mania, in an effort to more clearly define necessary targets of first-line medications, lithium and valproic acid, and to discover novel mechanisms with the hope of developing more effective therapeutics. Future studies will leverage new technologies and strategies for integrating animal and human data to reveal important insights into the etiology, pathophysiology, and treatment of BD.

Introduction

Bipolar disorder (BD) is a complex disease defined by periods of both mania and depression with euthymic or normal mood states between episodes. Manic episodes can consist of hyperactivity, elevated mood or agitation, racing thoughts, reckless behavior, little need for sleep, and sometimes psychosis. Depressive episodes as defined by the DSM V can include persistent sadness, fatigue, eating disturbances, sleep disturbances, suicidal thoughts, guilt and social withdrawal. The cause of BD is unknown and may involve both genetic and environmental factors (Shinozaki and Potash, 2014). The mood-stabilizing therapeutic effects of lithium (a salt) and valproate (an anticonvulsant) were discovered by accident and in the absence of any significant mechanistic understanding of BD (Can et al., 2014). While current treatments are generally effective for the reversal of manic episodes and preventing future episodes, these medications have limited, if any, efficacy on their own in the acute treatment of depressive episodes (McInerney and Kennedy, 2014). Moreover, standard antidepressant medications used either as monotherapies, or in conjunction with mood stabilizers or antipsychotics, are generally ineffective for treating depressive episodes, and may induce mood switching in a subset of patients with rapid cycling BD (De Wilde and Doogan, 1982, Himmelhoch et al., 1982, Gijsman et al., 2004, Amsterdam and Shults, 2005, Sachs et al., 2007, McElroy et al., 2010, Sidor and Macqueen, 2011, McInerney and Kennedy, 2014). Although there are a few studies suggesting therapeutic efficacy of antidepressant monotherapy for bipolar depression, current recommendations indicate antidepressants be used only in combination with mood stabilizers if those first-line medications fail (McInerney and Kennedy, 2014). Despite their effectiveness in the treatment of mania, chronic treatment with current mood-stabilizing drugs often results in serious side effects that make patient compliance difficult and burdensome. Our understanding of the etiological mechanisms of BD is poor. Therefore, the use of appropriate animal models should ultimately aid in the development of novel, potentially more efficacious treatments for this complex disorder.

The screening of compound libraries in animal models could also prove fruitful in the search for new medications. Most of the early mechanistic studies of BD in animals have focused on changes that occur following the administration of lithium or other agents often on animals that are comparatively “normal”, which may limit the interpretability and applicability of these studies since lithium has very little effect on healthy individuals while having therapeutic effects on those suffering from mania (Calil et al., 1990). Therefore the changes in the brain that occur in wild-type rodents may not represent the same changes that occur in a rodent displaying mania-like behavior.

Section snippets

Evaluating animal models of BD: issues of face, predictive, and construct validity

The use of rodent models that cut across multiple types of validity is vitally important to our understanding of psychiatric diseases and the search for better treatments. Face validity refers to the extent to which an animal model recapitulates important features of the human disease, such as neuroanatomical, biochemical, and/or behavioral phenotypes. There are few, if any, neurobiological pathologies that are known, with any certainty, to be biomarkers of the psychiatric disease. Even single

Amphetamine (AMP)-induced hyperactivity

The initial animal models of human mania relied heavily on the induction of hyperactivity in response to drugs that modulate dopaminergic activity (Table 2). People with BD have higher urinary dopamine levels with the emergence of manic symptoms (Joyce et al., 1995). Furthermore, many studies have found that psychostimulants (such as AMP) can produce symptoms that resemble human mania in normal healthy subjects (Meyendorff et al., 1985, Peet and Peters, 1995, Cousins et al., 2009) as well as

Sleep deprivation and circadian rhythm disruption

Some labs have attempted to use environmental manipulations to induce manic-like symptoms in animals. Since it is well known that circadian rhythm disruption and sleep disturbances can often trigger manic episodes (Malkoff-Schwartz et al., 1998, McClung, 2007), researchers have used various sleep deprivation paradigms to model human mania (Gessa et al., 1995) (Table 2). These paradigms often involve placing a rat or mouse on a small platform (3–7 cm) surrounded by water for an extended period of

Genetic models of bipolar mania

Human genetic studies have identified many gene polymorphisms associated with psychiatric diseases, such as depression, anxiety, and BD, which implicate altered gene function in these disorders. Rodent models that leverage single-gene mutation, knockout, or transgenic technologies are highly valuable for understanding the impact of a specific gene, or polymorphism, on behavior and the underlying mechanisms, although there are several limitations in their ability to fully resemble the

The Black Swiss mice

The major disadvantages of using single-gene knockout, knockdown, or overexpressing, transgenic mouse models to study bipolar mania or depression are sometimes poor construct validity and poor translational interpretations of the findings. Most, if not all, of the genetic association studies, which have identified polymorphisms associated with BD, have small effect sizes, explaining very little of the genetic variance. Highly penetrant, large effect alleles associated with psychiatric disorders

Mood cycling mouse models: a focus on the role of circadian mechanisms of behavioral state switching

Over the past several decades, there have been attempts to model mood cycling in rodents. Many have used pharmacological or environmental triggers to induce behavioral state switching (see Young and Dulcis, 2015). More recently, researchers have employed circadian and/or sleep perturbations to affect behavior in rodent models with the intention to achieve higher construct, or etiological validity. Sleep and circadian disruptions are hallmarks of those suffering with BD and used as diagnostic

Future directions

The major challenge for the field of translational neuroscience will continue to be the development, investigation, and interpretability of animal models of psychiatric diseases. In the absence of known etiology of BD, models based on clinical observations should be positioned to provide greater impact on our understanding of the disease process. Collaborative efforts are necessary to integrate data across many pharmacological, environmental, and genetic models of BD in order to elucidate

Conclusions

Rodent models are limited in their ability to capture the entirety of human BD. The combination of pharmacological, environmental, and genetic approaches will continue to bring the field closer to understanding the environmental, biological, and genetic etiological factors of the human disease. Preclinical models are also useful for screening novel compounds or discovering the therapeutic mechanisms of current treatments. It is important to continue to elucidate the cellular and molecular

Acknowledgments

Studies from our group were funded by IMHRO, NARSAD, MH082876, DA023988, NS058339 and The McKnight Foundation.

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