ReviewAnimal models of bipolar mania: The past, present and future
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.
References (310)
- et al.
Comparison of fluoxetine, olanzapine, and combined fluoxetine plus olanzapine initial therapy of bipolar type I and type II major depression–lack of manic induction
J Affect Disord
(2005) - et al.
Effect of catecholamine depletion on lithium-induced long-term remission of bipolar disorder
Biol Psychiatry
(1999) - et al.
Functional identification of the mouse circadian Clock gene by transgenic BAC rescue
Cell
(1997) - et al.
Evaluation of the effects of lamotrigine, valproate and carbamazepine in a rodent model of mania
Behav Brain Res
(2005) - et al.
Effects of bright light treatment on depression- and anxiety-like behaviors of diurnal rodents maintained on a short daylight schedule
Behav Brain Res
(2009) - et al.
Effect of asenapine on manic and depressive symptoms in bipolar I patients with mixed episodes: results from post hoc analyses
J Affect Disord
(2013) - et al.
Insensitivity to future consequences following damage to human prefrontal cortex
Cognition
(1994) - et al.
The Iowa Gambling Task and the somatic marker hypothesis: some questions and answers
Trends Cogn Sci
(2005) - et al.
Behavioural sensitization to repeated sleep deprivation in a mice model of mania
Behav Brain Res
(2008) - et al.
Life events and social rhythms in bipolar spectrum disorders: an examination of social rhythm sensitivity
J Affect Disord
(2012)
Effects of lithium chloride injections on rank-related fighting, maternal aggression and locust-killing responses in naive and experienced ‘TO’ strain mice
Pharmacol Biochem Behav
Glutathione deficit during development induces anomalies in the rat anterior cingulate GABAergic neurons: relevance to schizophrenia
Neurobiol Dis
The effects of lithium carbonate on healthy volunteers: mood stabilization?
Biol Psychiatry
Molecular actions and clinical pharmacogenetics of lithium therapy
Pharmacol Biochem Behav
Effects of lithium on an amphetamine animal model of bipolar disorder
Prog Neuropsychopharmacol Biol Psychiatry
Nonphotic phase-shifting in clock mutant mice
Brain Res
Opportunities for bioinformatics in the classification of behavior and psychiatric disorders
Int Rev Neurobiol
The relationship of impulsivity to response inhibition and decision-making in remitted patients with bipolar disorder
Eur Psychiatry
Regulation of Akt and glycogen synthase kinase-3 beta phosphorylation by sodium valproate and lithium
Neuropharmacology
Fluvoxamine and chlorimipramine in endogenous depression
J Affect Disord
N-acetyl cysteine restores brain glutathione loss in combined 2-cyclohexene-1-one and d-amphetamine-treated rats: relevance to schizophrenia and bipolar disorder
Neurosci Lett
Open field is more sensitive than automated activity monitor in documenting ouabain-induced hyperlocomotion in the development of an animal model for bipolar illness
Prog Neuropsychopharmacol Biol Psychiatry
Antimanic efficacy of retigabine in a proposed mouse model of bipolar disorder
Behav Brain Res
Effect of the new antiepileptic drug retigabine in a rodent model of mania
Epilepsy Behav
Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative
Am J Hum Genet
Alkali metal cations: effects on aggression and adrenal enzymes
Pharmacol Biochem Behav
Sand rats see the light: short photoperiod induces a depression-like response in a diurnal rodent
Behav Brain Res
An animal model for mania: preliminary results
Prog Neuropsychopharmacol Biol Psychiatry
Efficacy of olanzapine and haloperidol in an animal model of mania
Prog Neuropsychopharmacol Biol Psychiatry
Examining ventral and dorsal prefrontal function in bipolar disorder: a functional magnetic resonance imaging study
Eur Psychiatry
Interpersonal and social rhythm therapy: managing the chaos of bipolar disorder
Biol Psychiatry
Sleep deprivation in the rat: an animal model of mania
Eur Neuropsychopharmacol
Multivariate assessment of locomotor behavior: pharmacological and behavioral analyses
Pharmacol Biochem Behav
Association between sodium- and potassium-activated adenosine triphosphatase alpha isoforms and bipolar disorders
Biol Psychiatry
Reduced striatal dopamine DA D2 receptor function in dominant-negative GSK-3 transgenic mice
Eur Neuropsychopharmacol
The relationships between clinical characteristics, alcohol and psychotropic exposure, and circadian gene expression in human postmortem samples of affective disorder and control subjects
Psychiatry Res
Beta-catenin is a target for the ubiquitin–proteasome pathway
EMBO J
Lack of insight may predict impaired decision making in manic patients
Bipolar Disord
Striatal dopamine transporter availability in unmedicated bipolar disorder
Bipolar Disord
Neuroanatomical profile of antimaniac effects of histone deacetylases inhibitors
Mol Neurobiol
An important role for cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors
Mol Psychiatry
Epigenetic signaling in psychiatric disorders: stress and depression
Dialogues Clin Neurosci
Normal levels of prepulse inhibition in the euthymic phase of bipolar disorder
Psychol Med
A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health
J Psychiatry Neurosci
Beyond cAMP: the regulation of Akt and GSK3 by dopamine receptors
Front Mol Neurosci
Deciding advantageously before knowing the advantageous strategy
Science
Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta
Science
Influence of CLOCK gene polymorphism on circadian mood fluctuation and illness recurrence in bipolar depression
Am J Med Genet B Neuropsychiatr Genet
Searching for unique endophenotypes for schizophrenia and bipolar disorder within neural circuits and their molecular regulatory mechanisms
Schizophr Bull
Physiological roles of axonal ankyrins in survival of premyelinated axons and localization of voltage-gated sodium channels
J Neurocytol
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