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Using Tests and Models to Assess Antidepressant-Like Activity in Rodents Ewa Kedzierska1*, Izabela Wach2

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Using Tests and Models to Assess Antidepressant-Like Activity in Rodents Ewa Kedzierska1*, Izabela Wach2 DOI: 10.1515/cipms-2016-0013 Curr. Issues Pharm. Med. Sci., Vol. 29, No. 2, Pages 61-65 Current Issues in Pharmacy and Medical Sciences Formerly ANNALES UNIVERSITATIS MARIAE CURIE-SKLODOWSKA, SECTIO DDD, PHARMACIA journal homepage: http://www.curipms.umlub.pl/ Using tests and models to assess antidepressant-like activity in rodents Ewa Kedzierska1*, Izabela Wach2 1 Chair and Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Chodzki 4A, 20-093 Lublin, Poland 2 Student Research Group at the Chair and Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Chodzki 4A, 20-093 Lublin, Poland ARTICLE INFO ABSTRACT Received 08 February 2016 In today's world, depression is one of the more prevalent forms of mental illness. According Accepted 10 March 2016 to WHO, about 10%-30% of all women and 7%-15% of all men are afflicted by depression Keywords: at least once in their life-times. Today, depression is assessed to be affecting 350 million depression, people. Regarding this issue, an important challenge for current psychopharmacology animal models, is to develop new, more effective pharmacotherapy and to understand the mechanism atidepressants. of action of known antidepressants. Furthermore, there is the necessity to improve the effectiveness of anti-depression treatment by way of bringing about an understanding of the neurobiology of this illness. In achieving these objectives, animal models of depression can be useful. Yet, presently, all available animal models of depression rely on two principles: the actions of known antidepressants or the responses to stress. In this paper, we present an overview of the most widely used animal tests and models that are employed in assessing antidepressant-like activity in rodents. These include amphetamine potentiation, reversal of reserpine action, the forced swimming test, the tail suspension test, learned helplessness, chronic mild stress and social defeat stress. Moreover, the advantages and major drawbacks of each model are also discussed. INTRODUCTION Currently, depression is one of the most prevalent psy- depression coming about is a deficit in the monoamine neu- chiatric diseases, and it comes with a complex and het- rotransmitters (noradrenaline and serotonin) in the central erogeneous pathology. This devastating mental illness is nervous system. The mechanism of action of most known behaviourally characterized by various symptoms, including antidepressants reveals the correctness of this theory, as depressed mood, irritability, low self-esteem, and feeling of drugs that increase the levels of these monoamines in the hopelessness, feelings of worthlessness and guilt, as well brain are efficacious in the treatment of depression. It should as a decreased ability to concentrate and to think. Other be noted, however, that several other systems are also impli- hallmarks of depression are decreased or increased appetite, cated in the mechanisms underlying the positive effect of weight loss or weight gain, insomnia or hypersomnia, low antidepressants in treatment of depression. In spite of being energy, fatigue, or increased agitation and decreased interest clinically effective, most current antidepressant drugs have in pleasurable stimuli (e.g. sex, food, social interactions). some imperfections, among these are slow onset and severe The most dangerous symptoms of depression are recur- side effects [25]. Therefore, the search continues for more rent thoughts of death and suicide [22]. This disease also promising antidepressant drugs, as well as for better tools worsens, or even initiates other somatic illnesses, such as for conducting such types of experiments. cardiovascular [21,9,23], endocrine diseases [27] and cancer Various stressors (particularly, chronic stressors) increase [18]. the risk of developing affective disorders in humans. A The most widespread accepted theory regarding depres- crucial import into the onset of depression are the alterations sion is that of the “Monoamine Hypothesis of Depression” in the hypothalamic-pituitary-adrenal (HPA) axis which are [6,36]. This theory establishes that the main reason for activated by acute and chronic stress. As a result of exces- sive activation of the HPA axis, the level of glucocorticoids * Corresponding author in the human system is increased. This causes a cascade e-mail: [email protected] of effects, as a sustained elevation of glucocorticoids may © 2016 Medical University of Lublin. This is an open access article distributed under the Creative Commons Attribution-NonComercial-No Derivs licence (http://creativecommons.org/licenses/by-nc-nd/3.0/) 61 Using tests and models to assess antidepressant-like activity in rodents Ewa Kedzierska, Izabela Wach Using tests and models to assess antidepressant-like activity in rodents damage the hippocampal neurons (particularly the CA3 All available animal models of depression are based on pyramidal neurons) and decrease the expression of brain- two principles: the actions of known antidepressants or the derived neurotrophic factor (BDNF) [11,12]. Additional responses to stress [41]. reasons for depression coming about are abnormalities in Preclinical animal tests and models are aimed at deter- the neural circuitry underlying the normal mood. mining the direction of drug action. In such work, the dif- Epidemiologic data show that about 40%-50% of the risk ference between test and model should be noticed. Tests are of depression is genetic, hence, depression can be consid- based on the interactions of potential antidepressants with ered to be a highly heritable disorder [9]. Unfortunately, the the tool substances (they are, in fact, behavioural assays for specific genes that confer this risk have still not been found. the effects of antidepressants on specific neurotransmitters), Yet, vulnerability to depression is only partly genetic. Envi- and are characterized by simplicity of procedure rules and ronmental triggers are also very important etiologic factors. short duration. In contrast, animal models simulate some Chronic stress, emotional trauma and viral infections may aspects of depression. A model, hence, can be defined as increase vulnerability to depression. Accordingly, depres- a particular state of a non-human organism which mimics sion in most people is activated by interactions between some features of human pathology. It provides a certain a genetic predisposition and certain encountered environ- degree of predictive validity. Animal models of depression mental factors. are distinguished by greater complexity and longer duration than are tests [13,42]. GENERAL CONSIDERATIONS ANIMAL TESTS BASED ON THE INTERACTION The modelling of depression in animals is invaluable, and BETWEEN POTENTIAL ANTIDEPRESSANTS AND the perfect animal model can enable a better understanding REFERENCE SUBSTANCES of the molecular, genetic and epigenetic factors that may evoke depression. Through the use of animal models, we Amphetamine potentiation gain an opportunity to generate a better insight into underly- Amphetamine potentiation is a classic antidepressant ing of depression. Moreover, animal models of depression screening test [10]. Indeed, a lot of the effects of amphet- are very useful in discovering new antidepressant medi- amine action (excessive locomotor activity, hypothermia, cations.There are a lot of difficulties in translating human lower body weight and increase in avoidance reaction) are mental illnesses into relevant tests utilizing rodents. Depres- potentiated by antidepressants. These effects are probably sion is a heterogeneous disorder, and a full psychiatric based on the fact that antidepressants impair the metabolism syndrome of this illness cannot be mimicked in laboratory of amphetamine in the liver. As a result, the level of amphet- animals. Indeed, some symptoms of depression are likely amine concentration in brain is increased (pharmacokinetic to be purely human features (e.g. low self-esteem, guilt and interaction) [8]. Other data show that all of antidepressants, suicidality). Other symptoms, however, such as helpless- apart from mianserin, increase the maximal response to ness, anhedonia and behavioural despair, can be easily rep- amphetamine (pharmacodynamic interaction) [7]. These licated and measured in rodents. To evaluate animal models dates suggest the utility of the amphetamine potentiation of depression we employ three main criteria: face validity, test as a screening test. construct validity and predictive validity. Unfortunately, this test is non-specific, sometimes it gives Face validity is a consideration of the appropriateness either false negative or false positive results. What is more, of test or model as a source of data on the compound under newer antidepressants (e.g. mianserin, trazodone) which investigation. It is understood as a similarity of depression are structurally dissimilar to tricyclics, do not potentiate model within the animal subject to the ethology, psychopa- the effects of amphetamine action, while other drugs that thology, symptomatology and treatment of the depression are not antidepressants also can potentiate this action [41]. disorder in humans, it is measure of external similarity, a Reversal of reserpine action kind of analogy. The term construct validity is utilized for the assessment of the empirical and theoretical parallels This is one of the first tests that have been employed between the modelled features in animal test subjects and in research on antidepressant-like
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