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

Abstract

Bipolar disorder (BD) is the sixth leading cause of disability in the world according to the World Health Organization and affects nearly 6 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.

Genetic disruption of ankyrin-G in adult mouse forebrain causes cortical synapse alteration and behavior reminiscent of bipolar disorder

“…Although there have been many attempts to develop genetic mouse models of schizophrenia (33), there have been relatively few reports of genetic mouse models of bipolar disorder, especially based on loci with replicated genome-wide significance in human genetic studies (34). In our conditional KO mouse model with forebrain deletion of ankyrin-G, we found behavioral changes reminiscent of aspects of human bipolar disorder and synaptic and cellular changes correlating with the behavior changes, although we appreciate that translation from mouse model to human disease must be done with caution.…”

Is Mania the Hypertension of the Mood? Discussion of A Hypothesis

“…In addition, amphetamine administration is an acknowledged animal model of mania [23, 45, 46]. At the same time, levodopa (L-Dopa) frequently evokes mania, but rather decreases than increases blood pressure [47, 48].…”

Lithium and valproate prevent methylphenidate-induced mania-like behaviors in the hole board test

“…However, manic episodes experienced by bipolar patients display a rich panel of symptoms [1]. Preclinical studies aimed to mimicking the symptoms experienced by bipolar patients could give additional information about the biological basis and pharmacological targets for bipolar mania [14]. In our study, methylphenidate increased hole interactions on the hole board apparatus both centrally and peripherally.…”

“…Differently, modeling mania may be more challenging since many symptoms are exclusively observed in human beings, which limit the approach [12,13]. The induction of hyperactivity in response to drugs that modulate dopaminergic activity is the most common [14].…”