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UPDATE ARTICLES • Rev. Bras. Psiquiatr. 35 (Suppl 2) • 2013 • https://doi.org/10.1590/1516-4446-2013-1168   copy

Contributions of animal models to the study of mood disorders

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Mood disorders are a leading cause of morbidity and mortality, yet their underlying pathophysiology remains unclear. Animal models serve as a powerful tool for investigating the neurobiological mechanisms underlying psychiatric disorders; however, no animal model developed to date can fully mimic the “corresponding” human psychiatric disorder. In this scenario, the development of different animal models contributes to our understanding of the neurobiology of these disorders and provides the possibility of preclinical pharmacologic screening. The present review seeks to provide a comprehensive overview of traditional and recent animal models, recapitulating different features and the possible pathologic mechanisms of mood disorders emulated by these models.

Introduction

Mood disorders are common and potentially devastating conditions, associated with high rates of suicide and disability.11. Belmaker RH, Bersudsky Y. Bipolar disorder: Treatment. Discov Med. 2004;4:415-20.,22. Kupfer DJ. The increasing medical burden in bipolar disorder. JAMA. 2005;293:2528-30. Even with proper use of current pharmacological treatments, most patients continue to have recurrent mood episodes, residual symptoms, functional impairment, psychosocial disability, and significant medical and psychiatric comorbidities. A better understanding of the pathophysiologic mechanisms of these disorders is a prerequisite for the design of new drugs and their implementation in clinical practice.33. Zarate CA Jr, Singh J, Manji HK. Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Biol Psychiatry. 2006;59:1006-20.

Recent advances in genetic, neurobiological, and pharmacological methodologies have helped the development of animal models, which has been an important tool to investigate new intracellular systems that may be involved in the specific pathophysiology of psychiatric disorders.44. Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L, et al. The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci. 2003;23:7311-6.,55. Manji HK, Chen G. PKC, MAP kinases and the bcl-2 family of proteins as long-term targets for mood stabilizers. Mol Psychiatry. 2002;7:S46-56. However, no animal model developed to date can fully mimic the “corresponding” human psychiatric disorder. A particular challenge of bipolar disorder (BD) is its complex, alternating clinical course, with recurrent mood swings, including manic, depressive, and mixed episodes, which make the development of an adequate animal model challenging.66. Machado-Vieira R, Kapczinski F, Soares JC. Perspectives for the development of animal models of bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:209-24. Nevertheless, traditional and promising new animal models that mimic certain attributes of depression or mania have been established and are being used to deepen our understanding of the underlying mechanisms of distinct mood disorders.

Ellenbroek & Cools77. Ellenbroek BA, Cools AR. Animal models with construct validity for schizophrenia. Behav Pharmacol. 1990;1:469-90. have proposed that the validity of animal models in psychiatric disorders should demonstrate the following three major criteria: face validity, construct validity, and predictive validity. Face validity represents how similarly the model can mimic the symptoms of a given illness, whereas construct validity is related to the ability of the model to reproduce some pathophysiological aspects of the illness. Finally, predictive validity evaluates whether the therapeutic agents used in the treatment of an illness can reverse the symptoms induced in the animal model.

For decades, the monoaminergic hypothesis of mood disorders has explained both their pathophysiology and the mechanisms of action of psychopharmaceuticals, and it has led to the production of several generations of antidepressants and mood stabilizers. Nevertheless, there are serious limitations to the current monoamine theory, and additional mechanisms, including hypothalamic-pituitary-adrenal (HPA) axis dysfunctions and neurodegenerative and inflammatory alterations, are potentially associated with the pathogenesis of mood disorders. Furthermore, recent studies have showed that epigenetic mechanisms such as histone modifications and DNA methylation could affect diverse pathways leading to depression-like behaviors in animal models.

This review seeks to provide a comprehensive overview of traditional and recent animal models, recapitulating their different features and the possible pathophysiology of mood disorders emulated by those models.

How can depressive-like and manic-like behaviors be evaluated in laboratory animals?

Researchers have long attempted to develop animal models that mimic the greatest possible number of specific physiological and behavioral changes observed in mood disorders. Some behavioral tests are of utmost importance to assessment of the face validity of an animal model, which demonstrates its ability to mimic the symptoms of depression or mania. These behavioral tests include the forced swimming test (FST), tail suspension test (TST), sucrose consumption test, and open-field test.

The FST is a behavioral test described first by Porsolt et al.88. Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature. 1977;266:730-2. in the rat and subsequently in the mouse.99. Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther. 1977;229:327-36. It is the most commonly used test to screen for antidepressant activity and to evaluate depressive-like behavior in animal models of depression. The test involves two individual exposures to a cylindrical tank filled with water in which rats cannot touch the bottom of the tank or escape. Rats are individually placed in the water-containing cylinder for 15 min (pre-test session), and when re-exposed 24 h later to the apparatus, are tested for 5 min (test session). The test session measures the time the animal spends without moving.88. Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature. 1977;266:730-2. In the mouse FST, the animals are individually forced to swim in an open cylindrical container (diameter 10 cm, height 25 cm) containing 19 cm of water (depth), and the total duration of immobility is measured for 6 min.99. Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther. 1977;229:327-36.,1010. Budni J, Lobato KR, Binfaré RW, Freitas AE, Costa AP, Martín-de-Saavedra MD, et al. Involvement of PI3K, GSK-3beta and PPARgamma in the antidepressant-like effect of folic acid in the forced swimming test in mice. J Psychopharmacol. 2012;26:714-23. Immobility in the FST has been interpreted as a manifestation of negative mood, representing a kind of hopelessness in the animal, reflecting lack of motivation, which is a frequently reported symptom of depression.88. Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature. 1977;266:730-2.,99. Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther. 1977;229:327-36.,1111. Petit-Demouliere B, Chenu F, Bourin M. Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology (Berl). 2005;177:245-55. As the FST, the TST was first described, by Steru et al.,1212. Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl). 1985;85:367-70. in mice. It is also widely used to screen for antidepressant activity. The tail suspension-induced state of immobility in animals is similar to human depression and is amenable to reversal by antidepressant drugs.1212. Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl). 1985;85:367-70.,1313. Yin C, Gou L, Liu Y, Yin X, Zhang L, Jia G, et al. Antidepressant-like effects of L-theanine in the forced swim and tail suspension tests in mice. Phytother Res. 2011;25:1636-9. This animal model is also based on despair or helpless behavior in response to an inescapable and confined space.

Although these behavioral tests have been widely utilized in many preclinical trials to screen new antidepressant-like drugs,1414. Réus GZ, Stringari RB, Ribeiro KF, Ferraro AK, Vitto MF, Cesconetto P, et al. Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain. Behav Brain Res. 2011;221:166-71.,1515. Budni J, Freitas AE, Binfaré RW, Rodrigues AL. Role of potassium channels in the antidepressant-like effect of folic acid in the forced swimming test in mice. Pharmacol Biochem Behav. 2012;101:148-54. they do not necessarily provide any insights about neurobiological aspects of depression.1616. Dzirasa K, Covington HE 3rd. Increasing the validity of experimental models for depression. Ann N Y Acad Sci. 2012;1265:36-45. The three major criticisms of these tests as a tool for preclinical studies focusing on discovery of new antidepressant-like drugs are: i) the stress is usually applied for only 5 min to normal rodents, which is very different from human depression; ii) classical antidepressants have an acute antidepressant-like effect, whereas in humans, a clinical response to antidepressant medication takes at least 3 to 4 weeks; iii) it remains unclear whether these tests are sensitive to non-monoaminergic drugs.1414. Réus GZ, Stringari RB, Ribeiro KF, Ferraro AK, Vitto MF, Cesconetto P, et al. Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain. Behav Brain Res. 2011;221:166-71.,1717. Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13:1161-9.

Another important preclinical test is the foot shock escape task, which evaluates the animal's ability to learn to escape when exposed firstly to an inescapable foot shock and, at a predetermined time in the future, to an escapable foot shock. Acute antidepressants are able to reduce escape latency and failures. This test is subject to the same criticisms as the FST and TST. Nevertheless, it has been proposed as a model of learned helplessness in mice.1414. Réus GZ, Stringari RB, Ribeiro KF, Ferraro AK, Vitto MF, Cesconetto P, et al. Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain. Behav Brain Res. 2011;221:166-71.,1818. Maier SF. Learned helplessness and animal models of depression. Prog Neuropsychopharmacol Biol Psychiatry. 1984;8:435-46. Many issues can be raised regarding the utility of learned helplessness/behavioral depression as a model of depression or antidepressant activity. Furthermore, as learned helplessness is sensitive to both antidepressant and anxiolytic drugs, it may be an animal model of either depression or anxiety.1919. Maier SF, Watkins LR. Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci Biobehav Rev. 2005;29:829-41.

According to the DSM-IV-TR, one of the major symptoms of depression is anhedonia, the loss of interest or pleasure in daily activities.2020. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967;6:278-96.,2121. Klein DF. Endogenomorphic depression. A conceptual and terminological revision. Arch Gen Psychiatry. 1974;31:447-54. In rats or mice, anhedonic-like behavior is commonly assessed by evaluating sucrose intake. Thus, a reduction in consumption of palatable liquids or food is generally considered to represent anhedonia.2222. Dang H, Chen Y, Liu X, Wang Q, Wang L, Jia W, et al. Antidepressant effects of ginseng total saponins in the forced swimming test and chronic mild stress models of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1417-24.,2323. Strekalova T, Steinbusch HW. Measuring behavior in mice with chronic stress depression paradigm. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:348-61.

The open-field test was developed by Calvin S. Hall in 19322424. Hall CS, Ballachey EL. A study of the rat's behavior in a field: a contribution to method in comparative psychology. University of California Publications in Psychology. 1932;6:1-12. to test rodent emotionality. This test is commonly used to provide a qualitative and quantitative measurement of exploratory and locomotor activity in rodents. The apparatus consists of an arena surrounded by high walls, to prevent escape, and the floor of the open field is divided into squares. In the test session, the number of square crossings, rearing, and time spent moving are used to assess the activity of the rodent. Automatic open-field apparatuses, which have software-linked infrared beams or video cameras to make the process easier and more accurate, are currently available. The open-field task is also often used to assess anxiety by including additional measures of defecation, time spent in the center of the field, and evaluation of the first few minutes of activity. The effects of stimulants on behavior have been widely used as an animal model of mania, because they induce psychomotor agitation, which is commonly observed during mania; besides, locomotor activity is easily measured in rats or mice using the open-field test.2525. Davies JA, Jackson B, Redfern PH. The effect of amantadine, L-dopa, (plus)-amphetamine and apomorphine on the acquisition of the conditioned avoidance response. Neuropharmacology. 1974;13:199-204.

26. Berggren U, Tallstedt L, Ahlenius S, Engel J. The effect of lithium on amphetamine-induced locomotor stimulation. Psychopharmacology (Berl). 1978;59:41-5.-2727. Gould TJ, Keith RA, Bhat RV. Differential sensitivity to lithium's reversal of amphetamine-induced open-field activity in two inbred strains of mice. Behav Brain Res. 2001;118:95-105.

It is important to mention that these behavioral tests in animals are not animal models of depression, as they only mimic some aspects of the depressive symptoms seen in humans, whereas animal models mimic a whole specific system disturbance related to the phenotype of depression.1212. Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl). 1985;85:367-70.

Animal models of depression

In accordance with the first theory of depression, the so-called monoaminergic hypothesis, many studies have demonstrated that patients with major depression have abnormalities in the neurotransmitters of the brain, particularly serotonin (5-hydroxytryptamine, 5-HT), noradrenaline, and, as demonstrated more recently, dopamine (DA). However, this theory alone cannot fully explain the neurobiology of depression; therefore, other neurotransmission systems and signaling pathways have been implicated in the pathophysiological mechanisms of depression, such as acetylcholine (ACh), glutamate, gamma-aminobutyric acid (GABA), and endogenous opiates.2828. Saricicek A, Esterlis I, Maloney KH, Mineur YS, Ruf BM, Muralidharan A, et al. Persistent beta2*-nicotinic acetylcholinergic receptor dysfunction in major depressive disorder. Am J Psychiatry. 2012;169:851-9.

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30. Miller JM, Hesselgrave N, Ogden RT, Sullivan GM, Oquendo MA, Mann JJ, et al. Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder. Biol Psychiatry. 2013;74:287-95.

31. Savitz JB, Drevets WC. Neuroreceptor imaging in depression. Neurobiol Dis. 2013;52:49-65.-3232. Yoon SJ, Lyoo IK, Haws C, Kim TS, Cohen BM, Renshaw PF. Decreased glutamate/glutamine levels may mediate cytidine's efficacy in treating bipolar depression: a longitudinal proton magnetic resonance spectroscopy study. Neuropsychopharmacology. 2009;34:1810-8. Functional imaging studies have shown that blood flow and glucose levels are higher in some parts of the brain (e.g., the frontal cortex, amygdala, thalamus, and lower parts of the striatum) of patients with major depression as compared with controls.

Furthermore, the majority of antidepressants currently prescribed are 5-HT reuptake inhibitors (SSRIs), which make more 5-HT available to synapses, and drugs acting selectively on both norepinephrine and 5-HT transporters (mixed 5-HT/norepinephrine reuptake inhibitors, SNRIs), which increase the concentration of both norepinephrine and 5-HT in the synaptic cleft. Chronic therapy with antidepressants decreases the anhedonic symptoms observed in depressive patients, reverses cognitive impairment, and increases neurogenesis.3333. Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat Med. 2001;7:541-7.,3434. McEwen BS, Olie JP. Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine. Mol Psychiatry. 2005;10:525-37.

Animal models of depression are widely used to induce depressive-like symptoms in such a way that these can be reversed by classic antidepressants. Therefore, it is necessary that these models have predictive, face, and construct validity. It has not yet been possible to develop an animal model that completely mimics the bio-psychosocial characteristics of depression in humans. However, many animal models reproduce some important aspects of the disorder, and are a used in research of new therapeutic targets for depression.1212. Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl). 1985;85:367-70.,3535. Razafsha M, Behforuzi H, Harati H, Wafai RA, Khaku A, Mondello S, et al. An updated overview of animal models in neuropsychiatry. Neuroscience. 2013;240:204-18.

Preclinical models of depression based on induction of chronic or acute stress, such as unpredictable chronic mild stress, early life stress (maternal deprivation), and restraint stress, are important to replicate etiological conditions of depression.3636. Murakami S, Imbe H, Morikawa Y, Kubo C, Senba E. Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly. Neurosci Res. 2005;53:129-39.

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47. Park HJ, Park HJ, Chae Y, Kim JW, Lee H, Chung JH. Effect of acupuncture on hypothalamic-pituitary-adrenal system in maternal separation rats. Cell Mol Neurobiol. 2011;31:1123-7.-4848. Reus GZ, Stringari RB, Ribeiro KF, Cipriano AL, Panizzutti BS, Stertz L, et al. Maternal deprivation induces depressive-like behaviour and alters neurotrophin levels in the rat brain. Neurochem Res. 2011;36:460-6. and restraint stress3636. Murakami S, Imbe H, Morikawa Y, Kubo C, Senba E. Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly. Neurosci Res. 2005;53:129-39.,4949. Naert G, Ixart G, Maurice T, Tapia-Arancibia L, Givalois L. Brain-derived neurotrophic factor and hypothalamic-pituitary-adrenal axis adaptation processes in a depressive-like state induced by chronic restraint stress. Mol Cell Neurosci. 2011;46:55-66. (different duration and stimuli type of stressful events) induce HPA axis hyperactivity. HPA axis hyperactivity is closely related to stressful life events, which are key factors in the etiopathogenesis of depressive episodes in patients. Stress hormone release in the bloodstream is usually observed in these individuals.5050. Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000;23:477-501.

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46. Plotsky PM, Meaney MJ. Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Brain Res Mol Brain Res. 1993;18:195-200.

47. Park HJ, Park HJ, Chae Y, Kim JW, Lee H, Chung JH. Effect of acupuncture on hypothalamic-pituitary-adrenal system in maternal separation rats. Cell Mol Neurobiol. 2011;31:1123-7.

48. Reus GZ, Stringari RB, Ribeiro KF, Cipriano AL, Panizzutti BS, Stertz L, et al. Maternal deprivation induces depressive-like behaviour and alters neurotrophin levels in the rat brain. Neurochem Res. 2011;36:460-6.-4949. Naert G, Ixart G, Maurice T, Tapia-Arancibia L, Givalois L. Brain-derived neurotrophic factor and hypothalamic-pituitary-adrenal axis adaptation processes in a depressive-like state induced by chronic restraint stress. Mol Cell Neurosci. 2011;46:55-66. The induction of stress in animals can cause remodeling of synaptic contacts on CRH neurons, contributing to the development of animal models of stress-related psychiatric disorders such as depression.5656. Miklos IH, Kovacs KJ. Reorganization of synaptic inputs to the hypothalamic paraventricular nucleus during chronic psychogenic stress in rats. Biol Psychiatry. 2012;71:301-8. The administration of classical antidepressants reverses stress-induced biochemical and behavioral changes.4242. Reus GZ, Dos Santos MA, Abelaira HM, Ribeiro KF, Petronilho F, Vuolo F, et al. Imipramine reverses alterations in cytokines and BDNF levels induced by maternal deprivation in adult rats. Behav Brain Res. 2013;242:40-6.,5757. Sanchez C, Gruca P, Papp M. R-citalopram counteracts the antidepressant-like effect of escitalopram in a rat chronic mild stress model. Behav Pharmacol. 2003;14:465-70.

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59. Christiansen SH, Olesen MV, Wortwein G, Woldbye DP. Fluoxetine reverts chronic restraint stress-induced depression-like behaviour and increases neuropeptide Y and galanin expression in mice. Behav Brain Res. 2011;216:585-91.

60. Moretti M, Colla A, de Oliveira Balen G, dos Santos DB, Budni J, de Freitas AE, et al. Ascorbic acid treatment, similarly to fluoxetine, reverses depressive-like behavior and brain oxidative damage induced by chronic unpredictable stress. J Psychiatr Res. 2012;46:331-40.-6161. Moretti M, Budni J, Dos Santos DB, Antunes A, Daufenbach JF, Manosso LM, et al. Protective effects of ascorbic acid on behavior and oxidative status of restraint-stressed mice. J Mol Neurosci. 2013;49:68-79.

The animal models of depression induced by different stressful stimuli (chronic mild stress, maternal deprivation, and restraint stress) reproduce alterations in the immune system,4242. Reus GZ, Dos Santos MA, Abelaira HM, Ribeiro KF, Petronilho F, Vuolo F, et al. Imipramine reverses alterations in cytokines and BDNF levels induced by maternal deprivation in adult rats. Behav Brain Res. 2013;242:40-6.,6262. Tagliari B, Tagliari AP, Schmitz F, da Cunha AA, Dalmaz C, Wyse AT. Chronic variable stress alters inflammatory and cholinergic parameters in hippocampus of rats. Neurochem Res. 2011;36:487-93.,6363. Voorhees JL, Tarr AJ, Wohleb ES, Godbout JP, Mo X, Sheridan JF, et al. Prolonged restraint stress increases IL-6, reduces IL-10, and causes persistent depressive-like behavior that is reversed by recombinant IL-10. PLoS One. 2013;8:e58488. another pathophysiological aspect found in depressive patients.6464. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65:732-41. Classical antidepressants can improve mood and response to treatment in these individuals.6464. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65:732-41.,6565. Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet. 2006;367:29-35. Rodents subjected to stressful stimuli such as chronic mild stress have shown elevated levels of interleukin (IL) 1β, IL-6 and tumor necrosis factor-alpha (TNF-α), indicating changes in the immune system.6262. Tagliari B, Tagliari AP, Schmitz F, da Cunha AA, Dalmaz C, Wyse AT. Chronic variable stress alters inflammatory and cholinergic parameters in hippocampus of rats. Neurochem Res. 2011;36:487-93. Moreover, our group found increased TNF-α and IL-β levels in the serum and CSF of maternally deprived rats. By contrast, this same animal model of depression induced reduction of serum IL-10 levels. These changes in immune markers were reversed by imipramine.4242. Reus GZ, Dos Santos MA, Abelaira HM, Ribeiro KF, Petronilho F, Vuolo F, et al. Imipramine reverses alterations in cytokines and BDNF levels induced by maternal deprivation in adult rats. Behav Brain Res. 2013;242:40-6. Corroborating the idea that cytokines are involved in the depressive-like symptoms of animal models of depression, Karson et al.6666. Karson A, Demirtas T, Bayramgurler D, Balci F, Utkan T. Chronic administration of infliximab (TNF-alpha inhibitor) decreases depression and anxiety-like behaviour in rat model of chronic mild stress. Basic Clin Pharmacol Toxicol. 2013;112:335-40. showed that administration of the TNF-α inhibitor infliximab in rats subjected to chronic mild stress caused a reduction of the depressive-like effect observed on this animal model of depression (increased immobility time during FST and anhedonia on sucrose preference test). The pathophysiological mechanisms of chronic restraint stress also involve inflammation, since Voorhees et al.6363. Voorhees JL, Tarr AJ, Wohleb ES, Godbout JP, Mo X, Sheridan JF, et al. Prolonged restraint stress increases IL-6, reduces IL-10, and causes persistent depressive-like behavior that is reversed by recombinant IL-10. PLoS One. 2013;8:e58488. showed that prolonged restraint stress elicited an increase in circulating IL-6 and decrease in serum IL-4 and IL-10 in mice. It is important to note that interleukins, especially IL-10, play an important role in regulation of the HPA axis. Therefore, reduced production of IL-10 can induce hyperactivity of the HPA axis as seen in depressed patients6767. Roque S, Correia-Neves M, Mesquita AR, Palha JA, Sousa N. Interleukin-10: a key cytokine in depression? Cardiovasc Psychiatry Neurol. 2009;2009:187894. and can be reproduced in animal models of depression.6363. Voorhees JL, Tarr AJ, Wohleb ES, Godbout JP, Mo X, Sheridan JF, et al. Prolonged restraint stress increases IL-6, reduces IL-10, and causes persistent depressive-like behavior that is reversed by recombinant IL-10. PLoS One. 2013;8:e58488.

Considering that depressed patients have lower levels of brain-derived neurotrophic factor (BDNF) and that antidepressant therapy has reversed this effect,6868. Dwivedi Y. Involvement of brain-derived neurotrophic factor in late-life depression. Am J Geriatr Psychiatry. 2013;21:433-49. animal models based on stress induction have also replicated this pathophysiological feature. In animals exposed to unpredictable chronic mild stress, BDNF (an important neurotrophic factor) is decreased, and this effect is reversed by antidepressant therapy.6969. Roceri M, Hendriks W, Racagni G, Ellenbroek BA, Riva MA. Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus. Mol Psychiatry. 2002;7:609-16. Moreover, reductions in both BDNF and cyclic AMP response element binding protein (CREB) expression are proposed to be associated with the anhedonic symptoms and learning-memory impairments observed in stressed animals.7070. Gronli J, Bramham C, Murison R, Kanhema T, Fiske E, Bjorvatn B, et al. Chronic mild stress inhibits BDNF protein expression and CREB activation in the dentate gyrus but not in the hippocampus proper. Pharmacol Biochem Behav. 2006;85:842-9. Furthermore, an animal model of depression induced by maternal deprivation and restraint stress was associated with a reduction of BDNF levels in rodent brains.3737. Abelaira HM, Reus GZ, Ribeiro KF, Zappellini G, Cipriano AL, Scaini G, et al. Lamotrigine treatment reverses depressive-like behavior and alters BDNF levels in the brains of maternally deprived adult rats. Pharmacol Biochem Behav. 2012;101:348-53.,4242. Reus GZ, Dos Santos MA, Abelaira HM, Ribeiro KF, Petronilho F, Vuolo F, et al. Imipramine reverses alterations in cytokines and BDNF levels induced by maternal deprivation in adult rats. Behav Brain Res. 2013;242:40-6.,4444. Reus GZ, Abelaira HM, Stringari RB, Fries GR, Kapczinski F, Quevedo J. Memantine treatment reverses anhedonia, normalizes corticosterone levels and increases BDNF levels in the prefrontal cortex induced by chronic mild stress in rats. Metab Brain Dis. 2012;27:175-82.,4848. Reus GZ, Stringari RB, Ribeiro KF, Cipriano AL, Panizzutti BS, Stertz L, et al. Maternal deprivation induces depressive-like behaviour and alters neurotrophin levels in the rat brain. Neurochem Res. 2011;36:460-6.

It is important to note that chronic mild stress and maternal deprivation are among the most widely used preclinical models of depression. Chronic mild stress exposure induces depressive-like behaviors in rats, such as anhedonia and increased immobility in the FST. The reversion of these effects by chronic antidepressant treatment makes chronic mild stress one of the most valid models of depression.7171. Willner P. Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology. 2005;52:90-110. The maternal deprivation paradigm is an animal model that has been used to study the long-term effects of child abuse and neglect. Experiments showed that rats subjected to trauma and stress early in life exhibit depressive behavior at a later stage in life; these findings mimic the clinical conditions seen in humans. It is apparent that adverse events occurring early in life may affect the development and maturation of the brain.7272. Vazquez V, Farley S, Giros B, Dauge V. Maternal deprivation increases behavioural reactivity to stressful situations in adulthood: suppression by the CCK2 antagonist L365,260. Psychopharmacology (Berl). 2005;181:706-13.

In addition to studying different ways to manipulate animals in order to induce depressive symptoms, the removal of brain structures may be an effective alternative to study behavioral and neurobiological parameters associated with depression. In this regard, the bilateral removal of the olfactory bulbs in rodents has been widely used as an animal model of depression. This results in serious behavioral, neurochemical, neuroendocrine, and neuroimmune alterations that tend to co-occur in clinically depressed patients7373. Masini CV, Holmes PV, Freeman KG, Maki AC, Edwards GL. Dopamine overflow is increased in olfactory bulbectomized rats: an in vivo microdialysis study. Physiol Behav. 2004;81:111-9.

74. Freitas AE, Machado DG, Budni J, Neis VB, Balen GO, Lopes MW, et al. Fluoxetine modulates hippocampal cell signaling pathways implicated in neuroplasticity in olfactory bulbectomized mice. Behav Brain Res. 2013;237:176-84.

75. Oral E, Aydin MD, Aydin N, Ozcan H, Hacimuftuoglu A, Sipal S, et al. How olfaction disorders can cause depression? The role of habenular degeneration. Neuroscience. 2013;240:63-9.-7676. Rinwa P, Kumar A, Garg S. Suppression of neuroinflammatory and apoptotic signaling cascade by curcumin alone and in combination with piperine in rat model of olfactory bulbectomy induced depression. PLoS One. 2013;8:e61052. and can be restored by treatment with classical antidepressants.7777. Song C, Leonard BE. The olfactory bulbectomised rat as a model of depression. Neurosci Biobehav Rev. 2005;29:627-47.

78. Jarosik J, Legutko B, Unsicker K, von Bohlen Und Halbach O. Antidepressant-mediated reversal of abnormal behavior and neurodegeneration in mice following olfactory bulbectomy. Exp Neurol. 2007;204:20-8.

79. Breuer ME, Chan JS, Oosting RS, Groenink L, Korte SM, Campbell U, et al. The triple monoaminergic reuptake inhibitor DOV 216,303 has antidepressant effects in the rat olfactory bulbectomy model and lacks sexual side effects. Eur Neuropsychopharmacol. 2008;18:908-16.-8080. Breuer ME, Groenink L, Oosting RS, Buerger E, Korte M, Ferger B, et al. Antidepressant effects of pramipexole, a dopamine D3/D2 receptor agonist, and 7-OH-DPAT, a dopamine D3 receptor agonist, in olfactory bulbectomized rats. Eur J Pharmacol. 2009;616:134-40. In rats, olfactory bulbectomy induces depressive-like behavioral and physiological alterations such as anorexia, nutritional disorders, weight loss, psychomotor retardation, sexual aversion, decreased grooming behavior, reduced social interaction, increased immobility time in the FST, and anhedonia.7474. Freitas AE, Machado DG, Budni J, Neis VB, Balen GO, Lopes MW, et al. Fluoxetine modulates hippocampal cell signaling pathways implicated in neuroplasticity in olfactory bulbectomized mice. Behav Brain Res. 2013;237:176-84.

75. Oral E, Aydin MD, Aydin N, Ozcan H, Hacimuftuoglu A, Sipal S, et al. How olfaction disorders can cause depression? The role of habenular degeneration. Neuroscience. 2013;240:63-9.-7676. Rinwa P, Kumar A, Garg S. Suppression of neuroinflammatory and apoptotic signaling cascade by curcumin alone and in combination with piperine in rat model of olfactory bulbectomy induced depression. PLoS One. 2013;8:e61052.,8181. Machado DG, Cunha MP, Neis VB, Balen GO, Colla A, Grando J, et al. Fluoxetine reverses depressive-like behaviors and increases hippocampal acetylcholinesterase activity induced by olfactory bulbectomy. Pharmacol Biochem Behav. 2012;103:220-9. Rodents subjected to ablation of the olfactory bulbs display HPA axis hyperactivity8181. Machado DG, Cunha MP, Neis VB, Balen GO, Colla A, Grando J, et al. Fluoxetine reverses depressive-like behaviors and increases hippocampal acetylcholinesterase activity induced by olfactory bulbectomy. Pharmacol Biochem Behav. 2012;103:220-9.

82. van Riezen H, Leonard BE. Effects of psychotropic drugs on the behavior and neurochemistry of olfactory bulbectomized rats. Pharmacol Ther. 1990;47:21-34.

83. Kelly JP, Wrynn AS, Leonard BE. The olfactory bulbectomized rat as a model of depression: an update. Pharmacol Ther. 1997;74:299-316.-8484. Song C, Zhang XY, Manku M. Increased phospholipase A2 activity and inflammatory response but decreased nerve growth factor expression in the olfactory bulbectomized rat model of depression: effects of chronic ethyl-eicosapentaenoate treatment. J Neurosci. 2009;29:14-22. as well as a reduction7676. Rinwa P, Kumar A, Garg S. Suppression of neuroinflammatory and apoptotic signaling cascade by curcumin alone and in combination with piperine in rat model of olfactory bulbectomy induced depression. PLoS One. 2013;8:e61052. or increase7474. Freitas AE, Machado DG, Budni J, Neis VB, Balen GO, Lopes MW, et al. Fluoxetine modulates hippocampal cell signaling pathways implicated in neuroplasticity in olfactory bulbectomized mice. Behav Brain Res. 2013;237:176-84.,8585. Hellweg R, Zueger M, Fink K, Hortnagl H, Gass P. Olfactory bulbectomy in mice leads to increased BDNF levels and decreased serotonin turnover in depression-related brain areas. Neurobiol Dis. 2007;25:1-7.,8686. Luo KR, Hong CJ, Liou YJ, Hou SJ, Huang YH, Tsai SJ. Differential regulation of neurotrophin S100B and BDNF in two rat models of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:1433-9. of BDNF levels in brain areas. Moreover, olfactory bulbectomy also induces elevation of TNF-α and IL-1β levels in the rat brain.7676. Rinwa P, Kumar A, Garg S. Suppression of neuroinflammatory and apoptotic signaling cascade by curcumin alone and in combination with piperine in rat model of olfactory bulbectomy induced depression. PLoS One. 2013;8:e61052.,8484. Song C, Zhang XY, Manku M. Increased phospholipase A2 activity and inflammatory response but decreased nerve growth factor expression in the olfactory bulbectomized rat model of depression: effects of chronic ethyl-eicosapentaenoate treatment. J Neurosci. 2009;29:14-22.

The interaction between genes and the environment plays a significant role in the pathogenesis of depression. Preclinical models of depression based on genetic manipulation can be powerful tools for exploring this relationship and possible therapeutic strategies.8787. Massart R, Mongeau R, Lanfumey L. Beyond the monoaminergic hypothesis: neuroplasticity and epigenetic changes in a transgenic mouse model of depression. Philos Trans R Soc Lond B Biol Sci. 2012;367:2485-94. In the field of genetic engineering, it is noteworthy that studies in humans provide the identification of genetic targets, which can contribute to the reproduction of transgenic animal models of depression that can be successfully translated to humans (construct validity).2525. Davies JA, Jackson B, Redfern PH. The effect of amantadine, L-dopa, (plus)-amphetamine and apomorphine on the acquisition of the conditioned avoidance response. Neuropharmacology. 1974;13:199-204.,8888. Bagdy G, Juhasz G, Gonda X. A new clinical evidence-based gene-environment interaction model of depression. Neuropsychopharmacol Hung. 2012;14:213-20. As depressed patients have reduced levels of 5-HT, as noted earlier, mice have been engineered to express a loss-of-function of Tph2, the rate-limiting enzyme in the brain 5-HT synthesis pathway, similar to that seen in humans.8989. Jacobsen JP, Medvedev IO, Caron MG. The 5-HT deficiency theory of depression: perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 2Arg439His knockin mouse. Philos Trans R Soc Lond B Biol Sci. 2012;367:2444-59. This genetic modification induced hyposerotonergia; in other words, it is a naturalistic model of 5-HT deficiency.9090. Beaulieu JM, Zhang X, Rodriguiz RM, Sotnikova TD, Cools MJ, Wetsel WC, et al. Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proc Natl Acad Sci U S A. 2008;105:1333-8.

91. Jacobsen JP, Siesser WB, Sachs BD, Peterson S, Cools MJ, Setola V, et al. Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice. Mol Psychiatry. 2012;17:694-704.-9292. Dzirasa K, Kumar S, Sachs BD, Caron MG, Nicolelis MA. Cortical-amygdalar circuit dysfunction in a genetic mouse model of serotonin deficiency. J Neurosci. 2013;33:4505-13. Beaulieu et al.9090. Beaulieu JM, Zhang X, Rodriguiz RM, Sotnikova TD, Cools MJ, Wetsel WC, et al. Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proc Natl Acad Sci U S A. 2008;105:1333-8. showed that homozygous and heterozygous Tph2 knockin mice displayed increased immobility time in the TST and elevated latencies to cross to the lighted compartment, as well as a reduction of activity in this compartment, on the dark-light emergence test. On the face of it, it can be inferred that 5-HT deficiency elicits anxiety-like and depressant-like behavior. These behavioral effects can be mediated by activation of glycogen synthase kinase 3 (GSK3),9090. Beaulieu JM, Zhang X, Rodriguiz RM, Sotnikova TD, Cools MJ, Wetsel WC, et al. Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proc Natl Acad Sci U S A. 2008;105:1333-8. an important signaling molecule involved in depression.9393. Maes M, Fisar Z, Medina M, Scapagnini G, Nowak G, Berk M. New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates--Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology. 2012;20:127-50.

Another potential target is the cannabinoid type I (CB1) receptor. CB1 knockout mice are another preclinical model of depression, based on the fact that activation of CB1 receptors is involved in the control of mood and emotion.9494. Valverde O, Torrens M. CB1 receptor-deficient mice as a model for depression. Neuroscience. 2012;204:193-206. These mice have shown anxiety-like9595. Maccarrone M, Valverde O, Barbaccia ML, Castane A, Maldonado R, Ledent C, et al. Age-related changes of anandamide metabolism in CB1 cannabinoid receptor knockout mice: correlation with behaviour. Eur J Neurosci. 2002;15:1178-86.,9696. Uriguen L, Perez-Rial S, Ledent C, Palomo T, Manzanares J. Impaired action of anxiolytic drugs in mice deficient in cannabinoid CB1 receptors. Neuropharmacology. 2004;46:966-73. and depressive-like behavior9797. Aso E, Ozaita A, Valdizan EM, Ledent C, Pazos A, Maldonado R, et al. BDNF impairment in the hippocampus is related to enhanced despair behavior in CB1 knockout mice. J Neurochem. 2008;105:565-72.

98. Aso E, Renoir T, Mengod G, Ledent C, Hamon M, Maldonado R, et al. Lack of CB1 receptor activity impairs serotonergic negative feedback. J Neurochem. 2009;109:935-44.-9999. Aso E, Ozaita A, Serra MA, Maldonado R. Genes differentially expressed in CB1 knockout mice: involvement in the depressive-like phenotype. Eur Neuropsychopharmacol. 2011;21:11-22. accompanied by increase in serum corticosterone levels and decreased BDNF levels in the hippocampus,9797. Aso E, Ozaita A, Valdizan EM, Ledent C, Pazos A, Maldonado R, et al. BDNF impairment in the hippocampus is related to enhanced despair behavior in CB1 knockout mice. J Neurochem. 2008;105:565-72. as well as alteration of serotonergic function.9898. Aso E, Renoir T, Mengod G, Ledent C, Hamon M, Maldonado R, et al. Lack of CB1 receptor activity impairs serotonergic negative feedback. J Neurochem. 2009;109:935-44. In addition to Tph2 and CB1, other gene polymorphisms can be found in depressive patients, involving the genes coding for the 5-HT transporter (5-HT1A, 5-HT1B, and 5-HT2A) and endocannabinoid 1 (CB1) receptors, tryptophan hydroxylase-2 (Tph2), CREB1, BDNF, and G protein-coupled inwardly-rectifying potassium channel (GIRK) genes, which are important to the development of mutant animal models of depression based on these genes.8888. Bagdy G, Juhasz G, Gonda X. A new clinical evidence-based gene-environment interaction model of depression. Neuropsychopharmacol Hung. 2012;14:213-20.

Nevertheless, these mutant animal models present several problems: i) genetic lesions in mice do not replicate all of the robust phenotypes seen in humans; ii) mutations are usually common to different psychiatric disorders, producing different phenotypes; iii) depression involves multiple genes of small and rare effect, while mutant animal models usually involve only one gene; iv) the manipulation of a single gene involved in depression, alone, contributes with a small risk of development of the disorder; therefore, mutant animal models can be considered as animal models of risk for the disorder rather than of the disorder itself.3535. Razafsha M, Behforuzi H, Harati H, Wafai RA, Khaku A, Mondello S, et al. An updated overview of animal models in neuropsychiatry. Neuroscience. 2013;240:204-18. Therefore, it is important to emphasize that there is great controversy about the use of genetic animal models as a tool for depression research, as the genetic association of known polymorphisms with depression is often weak. Furthermore, mutant models are only available for a small group of genes involved in the pathological mechanisms related to depression susceptibility. Nevertheless, genetic animal models are widely used.

In summary, preclinical models of depression still present several limitations, such as the acute nature of tests or models; the fact that many symptoms seen in humans cannot be assessed in animals; and the gender of animals. It is known that the prevalence of depression in humans is significantly higher in females, but most animal models of depression are replicated in males.100100. Kendler KS, Gardner CO, Prescott CA. Toward a comprehensive developmental model for major depression in women. Am J Psychiatry. 2002;159:1133-45.

101. Shively CA, Register TC, Friedman DP, Morgan TM, Thompson J, Lanier T. Social stress-associated depression in adult female cynomolgus monkeys (Macaca fascicularis). Biol Psychol. 2005;69:67-84.-102102. Schmidt PJ, Luff JA, Haq NA, Vanderhoof VH, Koziol DE, Calis KA, et al. Depression in women with spontaneous 46, XX primary ovarian insufficiency. J Clin Endocrinol Metab. 2011;96:E278-87. Despite these limitations, preclinical models of depression are extremely important tools for studying the neurobiology of depression and developing more effective therapeutic strategies.

Animal models of bipolar disorder

Researchers do not yet fully understand the underlying mechanism of BD pathophysiology, and a number of environmental factors may be involved, although a genetic predisposition has been clearly established. One theory is that BD might be linked to neurotransmitter system dysfunction. The neurotransmitter systems that seem to be involved in this psychiatric disorder are the dopaminergic, cholinergic, noradrenergic, serotoninergic, GABAergic and glutamatergic systems.103103. Pinsonneault JK, Han DD, Burdick KE, Kataki M, Bertolino A, Malhotra AK, et al. Dopamine transporter gene variant affecting expression in human brain is associated with bipolar disorder. Neuropsychopharmacology. 2011;36:1644-55.

104. Thomsen MS, Weyn A, Mikkelsen JD. Hippocampal alpha7 nicotinic acetylcholine receptor levels in patients with schizophrenia, bipolar disorder, or major depressive disorder. Bipolar Disord. 2011;13:701-7.

105. Wiste AK, Arango V, Ellis SP, Mann JJ, Underwood MD. Norepinephrine and serotonin imbalance in the locus coeruleus in bipolar disorder. Bipolar Disord. 2008;10:349-59.

106. Benes FM. Nicotinic receptors and functional regulation of GABA cell microcircuitry in bipolar disorder and schizophrenia. Handb Exp Pharmacol. 2012:401-17.-107107. Ginsberg SD, Hemby SE, Smiley JF. Expression profiling in neuropsychiatric disorders: emphasis on glutamate receptors in bipolar disorder. Pharmacol Biochem Behav. 2012;100:705-11.

BD presents a complex, alternating clinical course, with recurrent mood swings including manic and depressive episodes, making the development of an adequate animal model a challenge. Currently, there are no animal models with sufficient face, construct, and predictive validity to be considered an animal model of BD. However, the hallmark of BD is manic symptoms, which are related to dopaminergic hyperactivity. Thus, the animal model of mania induced by amphetamine (AMPH), even though it addresses only one pole of the disorder, is still the most useful model to study BD.108108. Kara NZ, Einat H. Rodent models for mania: practical approaches. Cell Tissue Res. 2013;354:191-201.

AMPH acts on the central nervous system by increasing DA efflux, inhibiting DA reuptake and inhibiting DA degradation by the enzyme monoamine oxidase.109109. Schaeffer JC, Cho AK, Fischer JF. Inhibition of synaptosomal accumulation of l-norepinephrine II: N-aryloxyalkylphentermines, quaternary d-amphetamines, and 3-aryloxypropylamines. J Pharm Sci. 1976;65:122-6.

110. Robinson JB. Stereoselectivity and isoenzyme selectivity of monoamine oxidase inhibitors. Enantiomers of amphetamine, N-methylamphetamine and deprenyl. Biochem Pharmacol. 1985;34:4105-8.-111111. Hoffman BB, Lefkowitz RJ. Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG, editors. Goodman & Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996. p. 199-248. A study showed that acute administration of 10 µM AMPH is sufficient to increase DA levels in striatal slices of rat.112112. Paszti-Gere E, Jakus J. Protein phosphatases but not reactive oxygen species play functional role in acute amphetamine-mediated dopamine release. Cell Biochem Biophys. 2013;66:831-41. Dopaminergic drugs, such as AMPH, are able to induce manic symptoms in both normal human volunteers113113. Strakowski SM, Sax KW. Progressive behavioral response to repeated d-amphetamine challenge: further evidence for sensitization in humans. Biol Psychiatry. 1998;44:1171-7. and BD subjects.114114. Anand A, Verhoeff P, Seneca N, Zoghbi SS, Seibyl JP, Charney DS, et al. Brain SPECT imaging of amphetamine-induced dopamine release in euthymic bipolar disorder patients. Am J Psychiatry. 2000;157:1108-14. Interestingly, higher urinary DA levels have been associated with the emergence of manic symptoms.115115. Joyce PR, Fergusson DM, Woollard G, Abbott RM, Horwood LJ, Upton J. Urinary catecholamines and plasma hormones predict mood state in rapid cycling bipolar affective disorder. J Affect Disord. 1995;33:233-43. In addition, a study has demonstrated that BD patients exhibit modifications in an allele of the DA transporter encoder, which may enhance DA levels in the brains of BD patients.103103. Pinsonneault JK, Han DD, Burdick KE, Kataki M, Bertolino A, Malhotra AK, et al. Dopamine transporter gene variant affecting expression in human brain is associated with bipolar disorder. Neuropsychopharmacology. 2011;36:1644-55. Moreover, Pantazopoulos et al.116116. Pantazopoulos H, Stone D, Walsh J, Benes FM. Differences in the cellular distribution of D1 receptor mRNA in the hippocampus of bipolars and schizophrenics. Synapse. 2004;54:147-55. showed abnormal expression of the D1 receptor in BD patients. In the same study, the researchers described an increase in the number of neurons expressing the D1 receptor.

Another important fact associated with AMPH-induced hyperactivity is the alteration in BDNF levels in the rat brain.117117. Macedo DS, Medeiros CD, Cordeiro RC, Sousa FC, Santos JV, Morais TA, et al. Effects of alpha-lipoic acid in an animal model of mania induced by D-amphetamine. Bipolar Disord. 2012;14:707-18.

118. Cechinel-Recco K, Valvassori SS, Varela RB, Resende WR, Arent CO, Vitto MF, et al. Lithium and tamoxifen modulate cellular plasticity cascades in animal model of mania. J Psychopharmacol. 2012;26:1594-604.-119119. Frey BN, Andreazza AC, Cereser KM, Martins MR, Valvassori SS, Reus GZ, et al. Effects of mood stabilizers on hippocampus BDNF levels in an animal model of mania. Life Sci. 2006;79:281-6. Several studies have demonstrated that the chronic administration of AMPH decreases BDNF levels in the cerebral tissues of rats.117117. Macedo DS, Medeiros CD, Cordeiro RC, Sousa FC, Santos JV, Morais TA, et al. Effects of alpha-lipoic acid in an animal model of mania induced by D-amphetamine. Bipolar Disord. 2012;14:707-18.

118. Cechinel-Recco K, Valvassori SS, Varela RB, Resende WR, Arent CO, Vitto MF, et al. Lithium and tamoxifen modulate cellular plasticity cascades in animal model of mania. J Psychopharmacol. 2012;26:1594-604.-119119. Frey BN, Andreazza AC, Cereser KM, Martins MR, Valvassori SS, Reus GZ, et al. Effects of mood stabilizers on hippocampus BDNF levels in an animal model of mania. Life Sci. 2006;79:281-6. BDNF is a protein secreted by the brain responsible for regulating neural circuit development and function. The actions of BDNF are controlled by neural activity and its functions include neuronal differentiation, growth, and plasticity. For this reason, the impairment in BDNF levels observed in BD patients may contribute to brain atrophy and progressive cognitive changes, both of which are observed in BD.120120. Park H, Poo MM. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci. 2013;14:7-23.

Several clinical studies have shown changes in BDNF levels in the brain and blood of BD patients. Dunham et al.121121. Dunham JS, Deakin JF, Miyajima F, Payton A, Toro CT. Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains. J Psychiatr Res. 2009;43:1175-84. showed decreased expression of hippocampal BDNF and its receptors in patients with BD and major depression. The studies of Rao et al.122122. Rao JS, Keleshian VL, Klein S, Rapoport SI. Epigenetic modifications in frontal cortex from Alzheimer's disease and bipolar disorder patients. Transl Psychiatry. 2012;2:e132. and D'Addario et al.123123. D'Addario C, Dell'Osso B, Palazzo MC, Benatti B, Lietti L, Cattaneo E, et al. Selective DNA methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII. Neuropsychopharmacology. 2012;37:1647-55. suggest that changes in BDNF levels in BD patients are linked to epigenetic changes, such as hypo- and hypermethylation of DNA regions associated with BDNF expression. Additionally, histone deacetylases (HDAC) have been described as a potentially promising target for treatment of several neurological disorders.124124. Graff J, Tsai LH. Histone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci. 2013;14:97-111. HDAC inhibitors (HDACi) increase histone acetylation, which diminishes the affinity between histone proteins and DNA and thus facilitates gene transcription.125125. Brownell JE, Allis CD. Special HATs for special occasions: linking histone acetylation to chromatin assembly and gene activation. Curr Opin Genet Dev. 1996;6:176-84.,126126. Shahbazian MD, Grunstein M. Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem. 2007;76:75-100.

Valproate (VPA), an anticonvulsant and mood-stabilizing drug, has been characterized as an HDACi.127127. Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001;20:6969-78. Several studies have shown that VPA has neuroprotective effects, suggesting that the therapeutic mechanisms of this drug involve, at least in part, the inhibition of HDAC.128128. Chen PS, Peng GS, Li G, Yang S, Wu X, Wang CC, et al. Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry. 2006;11:1116-25.

129. Dou H, Birusingh K, Faraci J, Gorantla S, Poluektova LY, Maggirwar SB, et al. Neuroprotective activities of sodium valproate in a murine model of human immunodeficiency virus-1 encephalitis. J Neurosci. 2003;23:9162-70.-130130. Leng Y, Chuang DM. Endogenous alpha-synuclein is induced by valproic acid through histone deacetylase inhibition and participates in neuroprotection against glutamate-induced excitotoxicity. J Neurosci. 2006;26:7502-12. Recently, it was demonstrated that microinjection of sodium butyrate (SB) and VPA, two HDACi, in the ventricle, amygdala, striatum, and prefrontal cortex blocked the hyperactivity induced by methamphetamine.131131. Arent CO, Valvassori SS, Fries GR, Stertz L, Ferreira CL, Lopes-Borges J, et al. Neuroanatomical profile of antimaniac effects of histone deacetylases inhibitors. Mol Neurobiol. 2011;43:207-14. In addition, it was also demonstrated that intraperitoneal SB and VPA administration reversed and prevented dextroamphetamine (d-AMPH)-related manic behavior. In addition, SB protected against d-AMPH-induced mitochondrial complex damage and oxidative stress in the brains of rats.132132. Moretti M, Valvassori SS, Varela RB, Ferreira CL, Rochi N, Benedet J, et al. Behavioral and neurochemical effects of sodium butyrate in an animal model of mania. Behav Pharmacol. 2011;22:766-72.,133133. Steckert AV, Valvassori SS, Varela RB, Mina F, Resende WR, Bavaresco DV, et al. Effects of sodium butyrate on oxidative stress and behavioral changes induced by administration of D-AMPH. Neurochem Int. 2013;62:425-32.

Oxidative stress is an important marker present in BD and, interestingly, appears to be associated with BDNF. There is evidence showing that oxidative stress may be increased in conditions where BDNF is described to be decreased in BD.134134. Andreazza AC, Cassini C, Rosa AR, Leite MC, de Almeida LM, Nardin P, et al. Serum S100B and antioxidant enzymes in bipolar patients. J Psychiatr Res. 2007;41:523-9.,135135. Kapczinski F, Frey BN, Andreazza AC, Kauer-Sant'Anna M, Cunha AB, Post RM. Increased oxidative stress as a mechanism for decreased BDNF levels in acute manic episodes. Rev Bras Psiquiatr. 2008;30:243-5. Furthermore, preclinical studies using animal models of mania induced by AMPH have shown that the mood stabilizers lithium and VPA increase BDNF levels and protect the rat brain against oxidative damage.119119. Frey BN, Andreazza AC, Cereser KM, Martins MR, Valvassori SS, Reus GZ, et al. Effects of mood stabilizers on hippocampus BDNF levels in an animal model of mania. Life Sci. 2006;79:281-6.,136136. Frey BN, Valvassori SS, Reus GZ, Martins MR, Petronilho FC, Bardini K, et al. Effects of lithium and valproate on amphetamine-induced oxidative stress generation in an animal model of mania. J Psychiatry Neurosci. 2006;31:326-32. Therefore, we suggest that a good mood-stabilizing drug, besides acting on behavior, must act against oxidative stress and modulate BDNF levels in BD patients.

In addition to SB, several new possible mood stabilizers have been tested in animal models and some have demonstrated good results. In the absence of a precise pathophysiological characterization of BD, researchers have tested substances that act on the molecular targets of mood stabilizers, especially lithium and VPA. Protein kinase C (PKC) is a downstream biochemical target of lithium and VPA, and it has been suggested that the action of mood stabilizers on this protein may be the starting point for their antimanic effect.33. Zarate CA Jr, Singh J, Manji HK. Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Biol Psychiatry. 2006;59:1006-20.,137137. Manji HK, Lenox RH. Ziskind-Somerfeld Research Award. Protein kinase C signaling in the brain: molecular transduction of mood stabilization in the treatment of manic-depressive illness. Biol Psychiatry. 1999;46:1328-51. PKC has many functions in the neuron, including that of facilitating neurotransmitter release, neuronal excitability, and neuronal plasticity.138138. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992;258:607-14. Lithium and VPA attenuate PKC function, while promanic psychostimulants activate it, suggesting that PKC modulation plays a critical role in the treatment of mania.139139. Einat H, Manji HK. Cellular plasticity cascades: genes-to-behavior pathways in animal models of bipolar disorder. Biol Psychiatry. 2006;59:1160-71. In addition, several clinical studies have shown that tamoxifen (TMX) - a PKC inhibitor - is effective in treating acute mania.140140. Zarate CA Jr, Singh JB, Carlson PJ, Quiroz J, Jolkovsky L, Luckenbaugh DA, et al. Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Bipolar Disord. 2007;9:561-70.

141. Yildiz A, Guleryuz S, Ankerst DP, Ongür D, Renshaw PF. Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen. Arch Gen Psychiatry. 2008;65:255-63.-142142. Amrollahi Z, Rezaei F, Salehi B, Modabbernia AH, Maroufi A, Esfandiari GR, et al. Double-blind, randomized, placebo-controlled 6-week study on the efficacy and safety of the tamoxifen adjunctive to lithium in acute bipolar mania. J Affect Disord. 2011;129:327-31. Based on these observations, PKC inhibition was proposed as a promising therapeutic mechanism in the treatment of BD.143143. DiazGranados N, Zarate CA Jr. A review of the preclinical and clinical evidence for protein kinase C as a target for drug development for bipolar disorder. Curr Psychiatry Rep. 2008;10:510-9. Recently, our laboratory showed that TMX protected against d-AMPH-induced hyperactivity, mitochondrial complex damage, and oxidative stress in the brains of rats. In addition, TMX as well as lithium increased levels of BDNF and Bcl-2, which are anti-apoptotic proteins.118118. Cechinel-Recco K, Valvassori SS, Varela RB, Resende WR, Arent CO, Vitto MF, et al. Lithium and tamoxifen modulate cellular plasticity cascades in animal model of mania. J Psychopharmacol. 2012;26:1594-604. The number of potential new drugs tested in animal models is growing, which helps further our knowledge of the pathophysiology of BD and supports the development of better drugs for the treatment of this disorder.

In 1983, El-Mallakh144144. el-Mallakh RS. The Na,K-ATPase hypothesis for manic-depression. I. General considerations. Med Hypotheses. 1983;12:253-68. described a hypothesis about BD pathophysiology. This new hypothesis was presented to explain and integrate experimental and clinical observations of bipolar psychosis. This model is based on alterations in the activity of the sodium, potassium-activated adenosine triphosphatase (Na+, K+-ATPase) pump. In his review, El-Mallakh suggested that a reduction in the activity of Na+, K+-ATPase can be responsible for both phases of BD.144144. el-Mallakh RS. The Na,K-ATPase hypothesis for manic-depression. I. General considerations. Med Hypotheses. 1983;12:253-68. The Na+, K+-ATPase is a major plasma membrane transporter for sodium and potassium that maintains and reestablishes, after each depolarization, the electrochemical gradient of the neuron.145145. El-Mallakh RS, Schurr A, Payne RS, Li R. Ouabain induction of cycling of multiple spike responses in hippocampal slices is delayed by lithium. J Psychiatr Res. 2000;34:115-20. Therefore, changes in Na+, K+-ATPase activity can lead to changes in neuronal activity and, consequently, behavioral changes.

It has been well established that blood Na+, K+-ATPase enzyme activity is reduced in BD patients.146146. Huff MO, Li XP, Ginns E, El-Mallakh RS. Effect of ethacrynic acid on the sodium- and potassium-activated adenosine triphosphatase activity and expression in Old Order Amish bipolar individuals. J Affect Disord. 2010;123:303-7.

147. Li R, El-Mallakh RS. Differential response of bipolar and normal control lymphoblastoid cell sodium pump to ethacrynic acid. J Affect Disord. 2004;80:11-7.-148148. Antia IJ, Smith CE, Wood AJ, Aronson JK. The upregulation of Na+,K(+)-ATPase pump numbers in lymphocytes from the first-degree unaffected relatives of patients with manic depressive psychosis in response to in vitro lithium and sodium ethacrynate. J Affect Disord. 1995;34:33-9. Rose et al.149149. Rose AM, Mellett BJ, Valdes R Jr, Kleinman JE, Herman MM, Li R, et al. Alpha 2 isoform of the Na,K-adenosine triphosphatase is reduced in temporal cortex of bipolar individuals. Biol Psychiatry. 1998;44:892-7. have demonstrated reduced expression of the α2 isoform of Na+, K+-ATPase in the brain of subjects with BD. Another study demonstrated that genetic variations in Na+, K+-ATPase are associated with BD.150150. Goldstein I, Lerer E, Laiba E, Mallet J, Mujaheed M, Laurent C, et al. Association between sodium- and potassium-activated adenosine triphosphatase alpha isoforms and bipolar disorders. Biol Psychiatry. 2009;65:985-91. In addition, it has been found that subconvulsive doses of ouabain (OUA), a potent Na+, K+-ATPase inhibitor, produce a dose-related increased in locomotor activity, which is considered a manic-like behavior, in rats.151151. el-Mallakh RS, Wyatt RJ. The Na,K-ATPase hypothesis for bipolar illness. Biol Psychiatry. 1995;37:235-44. Together, these studies suggest that a small reduction in sodium pump activity may alter the excitability of neurons, producing both manic and depressive symptoms.

More recently, the animal model of mania induced by OUA has gained considerable attention. The intracerebroventricular (ICV) injection of OUA in rats mimics some manic symptoms, which are reverted by administration of classical mood stabilizers, such as lithium and VPA.152152. El-Mallakh RS, El-Masri MA, Huff MO, Li XP, Decker S, Levy RS. Intracerebroventricular administration of ouabain as a model of mania in rats. Bipolar Disord. 2003;5:362-5. Erratum in: Bipolar Disord. 2007;9:314.

153. Riegel RE, Valvassori SS, Elias G, Réus GZ, Steckert AV, de Souza B, et al. Animal model of mania induced by ouabain: Evidence of oxidative stress in submitochondrial particles of the rat brain. Neurochem Int. 2009;55:491-5.-154154. Jornada LK, Moretti M, Valvassori SS, Ferreira CL, Padilha PT, Arent CO, et al. Effects of mood stabilizers on hippocampus and amygdala BDNF levels in an animal model of mania induced by ouabain. J Psychiatr Res. 2010;44:506-10. Banerjee et al.155155. Banerjee U, Dasgupta A, Rout JK, Singh OP. Effects of lithium therapy on Na+-K+-ATPase activity and lipid peroxidation in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2012;37:56-61. found a significant decrease in Na+, K+-ATPase activity and increased lipid peroxidation in the serum of BD patients. In the same study, the authors demonstrated that lithium induces improvement in enzyme activity and a significant reduction in lipid peroxidation. Animal model studies have shown that manic-like hyperactivity induced by OUA is associated with severe brain damage by increasing formation of lipid and protein oxidation products and decrease of BDNF levels in the rat brain.154154. Jornada LK, Moretti M, Valvassori SS, Ferreira CL, Padilha PT, Arent CO, et al. Effects of mood stabilizers on hippocampus and amygdala BDNF levels in an animal model of mania induced by ouabain. J Psychiatr Res. 2010;44:506-10.,156156. Jornada LK, Valvassori SS, Steckert AV, Moretti M, Mina F, Ferreira CL, et al. Lithium and valproate modulate antioxidant enzymes and prevent ouabain-induced oxidative damage in an animal model of mania. J Psychiatr Res. 2011;45:162-8.

Moreover, it has been shown that activity of the enzymes catalase (CAT) and superoxide dismutase (SOD) is altered in the brain and cerebrospinal fluid of rats subjected to the animal model of mania induced by OUA.156156. Jornada LK, Valvassori SS, Steckert AV, Moretti M, Mina F, Ferreira CL, et al. Lithium and valproate modulate antioxidant enzymes and prevent ouabain-induced oxidative damage in an animal model of mania. J Psychiatr Res. 2011;45:162-8.

157. Brocardo PS, Budni J, Pavesi E, Franco JL, Uliano-Silva M, Trevisan R, et al. Folic acid administration prevents ouabain-induced hyperlocomotion and alterations in oxidative stress markers in the rat brain. Bipolar Disord. 2010;12:414-24.

158. Riegel RE, Valvassori SS, Moretti M, Ferreira CL, Steckert AV, de Souza B, et al. Intracerebroventricular ouabain administration induces oxidative stress in the rat brain. Int J Dev Neurosci. 2010;28:233-7.-159159. Bruning CA, Prigol M, Luchese C, Pinton S, Nogueira CW. Diphenyl diselenide ameliorates behavioral and oxidative parameters in an animal model of mania induced by ouabain. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38:168-74. Brocardo et al.157157. Brocardo PS, Budni J, Pavesi E, Franco JL, Uliano-Silva M, Trevisan R, et al. Folic acid administration prevents ouabain-induced hyperlocomotion and alterations in oxidative stress markers in the rat brain. Bipolar Disord. 2010;12:414-24. also demonstrated that glutathione peroxidase and glutathione reductase levels are decreased in the hippocampus and cortex of rats after ICV OUA injection. Interestingly, lithium and VPA were able to protect the brain against the protein and lipid damage and SOD and CAT changes induced by OUA in rats.156156. Jornada LK, Valvassori SS, Steckert AV, Moretti M, Mina F, Ferreira CL, et al. Lithium and valproate modulate antioxidant enzymes and prevent ouabain-induced oxidative damage in an animal model of mania. J Psychiatr Res. 2011;45:162-8.

Machado-Vieira et al.160160. Machado-Vieira R, Andreazza AC, Viale CI, Zanatto V, Cereser V Jr, da Silva Vargas R, et al. Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects. Neurosci Lett. 2007;421:33-6. demonstrated an increase of lipid damage in the plasma of BD patients during initial episodes of mania, when compared with healthy controls. This study also reported an increase of SOD and CAT, which are natural antioxidant defenses. Treatment with lithium decreased the lipid damage and CAT and SOD level alterations, demonstrating an antioxidant effect and a potential role for these effects in the pathophysiology and treatment of BD. Some antioxidant substances have been tested in the animal model of mania induced by OUA. Administration of folic acid, a potent antioxidant, prevented OUA-induced behavioral alterations, lipid damage, and glutathione peroxidase and glutathione reductase changes in the rat brain.157157. Brocardo PS, Budni J, Pavesi E, Franco JL, Uliano-Silva M, Trevisan R, et al. Folic acid administration prevents ouabain-induced hyperlocomotion and alterations in oxidative stress markers in the rat brain. Bipolar Disord. 2010;12:414-24. Diphenyl diselenide, an organoselenium component of antioxidant enzymes, also reverted behavioral alterations attenuated lipid and protein damage, and prevented the increase of SOD and CAT induced by OUA.159159. Bruning CA, Prigol M, Luchese C, Pinton S, Nogueira CW. Diphenyl diselenide ameliorates behavioral and oxidative parameters in an animal model of mania induced by ouabain. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38:168-74.

Recently, it was demonstrated that ICV administration of OUA alters synaptic plasticity and DA release in the rat medial prefrontal cortex (mPFC). These findings suggested that alterations in synaptic plasticity and DA release in the mPFC might underlie the mPFC dysfunctions that accompany OUA-induced manic-like behavior. These OUA-induced alterations in synaptic plasticity can be prevented by pretreatment with lithium. This study highlights important aspects of this animal model, which is able to mimic behavioral changes seen in BD as well as two important pathophysiological alterations observed in this disorder: a decrease in Na+, K+-ATPase activity and an increase in extracellular DA.161161. Sui L, Song XJ, Ren J, Ju LH, Wang Y. Intracerebroventricular administration of ouabain alters synaptic plasticity and dopamine release in rat medial prefrontal cortex. J Neural Transm. 2013;120:1191-9.

Considering the search for animal models of BD that mimic the symptoms of this disorder more accurately, preclinical models based on circadian rhythm disturbances are being developed. Circadian rhythms are present in many organisms and are controlled by a central biological clock in the suprachiasmatic nucleus. Their main function is to regulate biological processes with circadian periodicity.162162. Harvey AG. Sleep and circadian rhythms in bipolar disorder: seeking synchrony, harmony, and regulation. Am J Psychiatry. 2008;165:820-9.

163. Quera Salva MA, Hartley S. Mood disorders, circadian rhythms, melatonin and melatonin agonists. J Cent Nerv Syst Dis. 2012;4:15-26.-164164. Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381:1672-82. Circadian rhythm abnormalities have been associated with BD, but its potential role in the pathophysiology of BD is still poorly understood.164164. Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381:1672-82. Studies have found that life events that disrupt the social rhythm are associated with the onset of manic episodes in BD patients. It bears stressing that disruption of daily routines leads to circadian rhythm instability, which can cause affective episodes.165165. Malkoff-Schwartz S, Frank E, Anderson B, Sherrill JT, Siegel L, Patterson D, et al. Stressful life events and social rhythm disruption in the onset of manic and depressive bipolar episodes: a preliminary investigation. Arch Gen Psychiatry. 1998;55:702-7.,166166. Malkoff-Schwartz S, Frank E, Anderson BP, Hlastala SA, Luther JF, Sherrill JT, et al. Social rhythm disruption and stressful life events in the onset of bipolar and unipolar episodes. Psychol Med. 2000;30:1005-16. Taking this into account, Frank et al.167167. Frank E, Kupfer DJ, Thase ME, Mallinger AG, Swartz HA, Fagiolini AM, et al. Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder. Arch Gen Psychiatry. 2005;62:996-1004. showed that interpersonal and social rhythm therapy can prevented the emergence of new episodes. Therefore, considering that sleep abnormalities are seen in patients with BD, mainly in manic states,168168. Hudson JI, Lipinski JF, Keck PE Jr, Aizley HG, Lukas SE, Rothschild AJ, et al. Polysomnographic characteristics of young manic patients. Comparison with unipolar depressed patients and normal control subjects. Arch Gen Psychiatry. 1992;49:378-83.

169. Plante DT, Winkelman JW. Sleep disturbance in bipolar disorder: therapeutic implications. Am J Psychiatry. 2008;165:830-43.-170170. Giglio LM, Andreazza AC, Andersen M, Ceresér KM, Walz JC, Sterz L, et al. Sleep in bipolar patients. Sleep Breath. 2009;13:169-73. an animal model of paradoxical sleep deprivation in rodents can reproduce mania-like symptoms.171171. Gessa GL, Pani L, Fadda P, Fratta W. Sleep deprivation in the rat: an animal model of mania. Eur Neuropsychopharmacol. 1995;5:89-93.

172. Benedetti F, Fresi F, Maccioni P, Smeraldi E. Behavioural sensitization to repeated sleep deprivation in a mice model of mania. Behav Brain Res. 2008;187:221-7.

173. Szabo ST, Machado-Vieira R, Yuan P, Wang Y, Wei Y, Falke C, et al. Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of mania. Neuropharmacology. 2009;56:47-55.-174174. Armani F, Andersen ML, Andreatini R, Frussa-Filho R, Tufik S, Galduróz JC. Successful combined therapy with tamoxifen and lithium in a paradoxical sleep deprivation-induced mania model. CNS Neurosci Ther. 2012;18:119-25. In fact, Gessa et al.171171. Gessa GL, Pani L, Fadda P, Fratta W. Sleep deprivation in the rat: an animal model of mania. Eur Neuropsychopharmacol. 1995;5:89-93. showed that animals subjected to sleep deprivation exhibit hyperactivity, irritability, aggressiveness, hypersexuality, and stereotypy. The opioid and dopaminergic systems appear to be involved in these effects.171171. Gessa GL, Pani L, Fadda P, Fratta W. Sleep deprivation in the rat: an animal model of mania. Eur Neuropsychopharmacol. 1995;5:89-93. Moreover, the behavioral changes observed in this animal model may be mediated, at least in part, by interaction with the PKC pathway, which may contribute to the pathophysiology of mania.173173. Szabo ST, Machado-Vieira R, Yuan P, Wang Y, Wei Y, Falke C, et al. Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of mania. Neuropharmacology. 2009;56:47-55. More recently, Armani et al.174174. Armani F, Andersen ML, Andreatini R, Frussa-Filho R, Tufik S, Galduróz JC. Successful combined therapy with tamoxifen and lithium in a paradoxical sleep deprivation-induced mania model. CNS Neurosci Ther. 2012;18:119-25. showed that sleep deprivation induces hyperlocomotion which is reversed by lithium.174174. Armani F, Andersen ML, Andreatini R, Frussa-Filho R, Tufik S, Galduróz JC. Successful combined therapy with tamoxifen and lithium in a paradoxical sleep deprivation-induced mania model. CNS Neurosci Ther. 2012;18:119-25. These studies contribute immensely to the search for an animal model that is closer to the ideal representation of BD.

The more an animal model mimics the aspects of the disorder, the more it would accelerate BD research by improving our understanding of the pathophysiology of the disorder and providing the possibility of preclinical pharmacologic screening.152152. El-Mallakh RS, El-Masri MA, Huff MO, Li XP, Decker S, Levy RS. Intracerebroventricular administration of ouabain as a model of mania in rats. Bipolar Disord. 2003;5:362-5. Erratum in: Bipolar Disord. 2007;9:314.

Conclusion

This review has discussed how the multiple animal models of depression and BD can help our understanding of the pathophysiology of these psychiatric disorders and research new targets for their therapy. However, the challenge faced by researchers is to reproduce, in the animal model, the greatest possible number of the symptoms and pathophysiologic changes seen in the human disorder. BD, which features a complex, alternating clinical course with recurrent mood swings including manic, depressive, and mixed episodes, poses a particular challenge for the development of an adequate animal model. It is clear that the development of suitable animal models would accelerate mood disorder research by improving understanding of the pathophysiology of the disorder and providing the possibility of preclinical pharmacologic screening.152152. El-Mallakh RS, El-Masri MA, Huff MO, Li XP, Decker S, Levy RS. Intracerebroventricular administration of ouabain as a model of mania in rats. Bipolar Disord. 2003;5:362-5. Erratum in: Bipolar Disord. 2007;9:314. Just as BD, major depression also lacks an animal model that mimics all the symptoms observed in depressed humans. However, the available animal models of depression are able to reproduce a larger number of symptoms which resemble the human disorder than the models currently available for BD. Despite all of these limitations, animal models are an important tool for investigation of the neurobiological mechanisms underlying psychiatric disorders, and appear to be a promising vehicle for preclinical screening of mood-stabilizing and antidepressant drugs.

We thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo è Pesquisa e Inovação do Estado de Santa Catarina (FAPESC), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and UNESC for the financial support provided. We also thank NM - Assessoria para Trabalhos Acadêmicos, who reviewed and corrected this article.

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