Keywords

Since the mid 1950s, neuroscience has thrived as a set of theories and techniques intending to provide answers regarding the functioning of the nervous system. Anchored to great progress in experimental pharmacology, which at that time aimed to understand the central and peripheral neurochemical functioning, in addition to the major mechanisms of the action of drugs used in the clinical treatment of several psychopathologies (anxiety, depression, schizophrenia), neuroscience has developed and improved many animal models.

These models have contributed and still play a determining role in the comprehension of the major mechanisms involved in developing and maintaining most of the psychopathologies that were identified in clinical reports. Clinical professionals, however, are not always able to understand and make appropriate usage of the data provided by experimental studies to support their patients.

Thus, this chapter has two main goals: (1) To present the main basis underlying the theory of experimental models in psychopathology; (2) To provide a checklist to simplify the understanding of the models by clinical professionals.

Animal Models in Psychopathology

The understanding of the concept of model is imperative to the science and it is based on a logical construction that differs from the research with an empirical basis from the theory itself, adopting its own steps and ways of generating knowledge. Thus, the concept of a model can be understood as the reduction of a complex fact into an ideal form, a paradigm, which enables being reproduced out of a simplified form, and is also comprised by its major defining elements.

A theoretical model can be better understood using constructs that account for clarifying or reproducing a phenomenon from reality [1]. Hence, a model picks up some variables out of reality and manipulates them so as to explain the variables with solid reproducibility. Therefore, the development of new models is a central activity in science.

In the study of health sciences, the scenario is not diverse because much of the research is conducted based on a complex fact, reproduced under a controlled situation which simulates conditions that are appropriate to the onset of the main elements that define the model, using some model organisms such as rats, mice, fish, dogs, as well as many others. During the process of construction of a model, three main elements can be indentified: the Zeitgeist (historical context), the punctuality, and the reducibility [2, 3].

The selection of a certain model in a given historical moment is influenced by demands related to the period when this model is developed, in addition to the group of researchers involved with it, restricting their contributions into a particular social focus of observation; this is so called Zeitgeist (spirit of the period of history). We can similarly assume that a certain model meets the criteria for defining itself as a model of something specific, namely, it is characterized as being the representation of a singular phenomenon in the world. We call this element punctuality. During the process of building a model, the choice for some elements that better define the model, ends up implying in a theoretical option for certain variables which are valued and identified as relevant, in detriment to the others. We call this element reducibility.

Furthermore, a particular model can also be valued or classified as a “good” or “bad” model, depending on the criteria. Such measurement is generally based on three main criteria: (1) its value in practical use, also known as predictive value; (2) its ability of generating new knowledge, also named construct value; and (3) its similarity with the proposed phenomenon, also called face value.

For our propose, we consider the set of disciplines in which behavior is the object of study as behavioral sciences. Along with psychology, they comprise sociology, anthropology, ecology, a considerable part of zoology, and the information sciences. In these sciences, the use of models for studying several kinds of natural phenomena or conditions simulating a natural phenomena has been widely used. However, for the study of disruptive behavior alterations, or psychopathologies, there is a displacement in the concept of model if compared withother biological and health sciences.

The concept of an animal model in psychopathology is not defined as the way the organism behaves. It is rather the manipulation of a set of variables that may generate a particular state in an organism, which in turn can be useful for studying a particular pathology. This displacement occurs as a result of the difficulty in defining a behavioral disease as such.

The concept of pathology is present with a set of criteria (a syndrome, a predictable time course, or an anatomopathological basis) met by few psychiatric disorders [4–6]. In general, the diagnosis of pathologies in behavioral sciences is restricted to the presented syndrome, given our relative unfamiliarity with anatomopathological alterations and with the time course of the nosological categories used for pathology classification. The Diagnostic and Statistical Manual of Mental Disorders - version IV (DSM-IV) [5, 6] extensively illustrates this.

The seeming fragility depicted by the displacement of a concept of a model based on the animal, to a concept based on the procedure, has allowed and still allows us to use several species in order to research the deviant behavior.

McKinney [7] suggests four questions that should be asked by a researcher, or even by a clinician who wants to evaluate an animal model of psychopathology: (1) Does this model describe the pathology causes and treatments? (2) Are the presented “symptoms” similar to what is observed in the symptomatology of the pathology? (3) Does the pathology and the model share a similar biological substrate? (4) Is it a specific model for a disorder or is it a modeling of human psychopathology aspects?

Mckinney’s proposal meets the general requirements for the construction of a model, presenting predictive value and face value, and, furthermore, he introduces a new question regarding the range of the model; namely, does the proposed model meet the criteria for a model of psychopathology, emotional reactivity, or even for a specific pathology?

In order to answer these questions, we need to list which behaviors (responses) of the animals exposed to the model are related to responses emitted by humans. Afterward, it will be necessary to evaluate which stimuli or dimensions of the stimuli are relevant to that animal, exposed to that particular situation.

Such considerations could be associated in a particular acquired knowledge, regarding the basic assumptions that define the psychopathology to be studied, as well as an extensive investigation regarding the ecology and ethology of the animal used in the model for psychopathology.

It is evident that understanding the study of experimental models as it has been approached in this text, implies assuming a biological substrate related to topography and function of the responses emitted by animals when they are exposed to certain situations. This substrate probably has the evolutionary basis relatively preserved along the changes undergone by species during the evolutionary process, so that certain features are similarly exhibited by different species [8, 9].

In general, a model of psychopathology can be defined as a set of stimuli aiming to mimic and measure the aspects considered essential in a determined psychopathological entity. These aspects may be topographic, of process, or even regarding sensitivity to drugs [2, 3, 10, 11], and in general, its description is made using a mixed vocabulary, combining words from different psychological approaches with words from research areas that have an interest in the model, such as pharmacology, ecology, physiology, among others [11].

Thus, before a model is accepted by the scientific community, a validation process occurs. This process consists of (1) describing similarities with the pathologies to be mimicked; (2) evaluating its capacity to react to drugs and other therapeutic manipulations commonly used to treat disorders; (3) evaluating its effectiveness in generating new treatments and management possibilities. The three abovementioned processes of validation are commonly known as face validity, pharmacological validity, and predictive validity, respectively [2]. Finally, apart from the above-cited characteristics of validity, the construction of a model is also deeply affected by social and historical conditions, the Zeitgeist [2].

Limits of the Concept of Model

The limits of the models are diverse and widely described in literature [12–14] However, researchers who propose to develop them, or even use existing models, frequently face many problems that end up affecting the validity and applicability of the models. Factors associated with costs of acquiring and keeping the organisms; differences in strains of the same species; sex differences; problems with breeding subjects in captivity; and the need for generating a considerable amount of data for publication (performing research in a shorter time) are some of the reasons why some models are not widespread.

Most of the clinical essays produce statistically fragile data because they have low levels of randomizing and blinding, reduced number of animals, and low ecologic importance. Such aspects lead to generating models that don not reflect realistic conditions and cannot be correlated to pathologies identified and treated in clinics.

A good example of these limits can be shown through two experimental models of depression: (1) The Porsolt forced swim test [15], which is a model in which the animal is placed in a tank filled with water and avoid reaching the bottom, so the time until the animal stops swimming and starts to float is recorded (latency). This could be a correlate of anhedonia, displayed by individuals suffering from depressive symptoms. (2) The tail suspension test [16], in which the subject is suspended by its tail at an altitude of at least 50 cm, and the immobility time is recorded, which could be also a correlate of anhedonia.

Both tests have a good predictive validity and are sensitive to acute and chronic administration of antidepressants, such as tricyclic antidepressants and selective serotonin (5-HT) reuptake inhibitors that are commonly used in clinics and have increased the latency for floating (forced swim) and decreased immobility time (tail suspension). However, when we refer to any kind of mood disorders, it should be noted that the DSM-IV [5] points out several criteria to be met that are difficult to replicate in the laboratory, particularly in species other than humans.

Such factors end up hindering the detection of behaviors that are presented by animals exposed to these models, and that could be somehow correlated to behaviors presented by a depressive subject. This difficulty ends up affecting its similarity with the pathologic framework of depression, weakening the face validity of these models, and impairing the development of new knowledge regarding the main mechanisms related to evolution and time course of the pathology, as well as the best ways to treat it.

Thus, just as it is necessary to understand and properly interpret an experimental model of a particular psychopathological entity, it is also important to attach great importance to limitations in the model being studied in order to avoid unreal statements.

A Guide to the Reading of Models for Clinical Professionals

What details must a clinical professional notice so as to fully understand a study regarding models? We believe that the clinician must keep in mind the following elements:

  1. (1)

    A model is not the pathology

    Models are theoretical tools used for researching. Although models such as the elevated plus-maze [17] are useful for the study of anxiety, in this model the rat does not suffer from generalized anxiety disorder. However, in this situation, the rat is very sensitive to drugs that act on this pathology.

  2. (2)

    Models are not determined by theoretical choices

    The choice for a model based on operant or respondent behavior, in a naturalistic situation or related to pharmacologic manipulation reflects the knowledge of the person performing the experiment regarding the pathology to be studied. Although this choice provides insight, it is impossible to reduce the pathology into this very same mechanism. This element is an extension of the former element.

  3. (3)

    Organisms have variations among themselves, according to strain, sex, or species, so the effect of a drug may vary among them.

    The antidepressant drugs used in clinics are mainly tricyclics and selective serotonin reuptake inhibitors. In rodents, they generally produce proactive effects over depressive-like behaviors, when administered in acute doses (a single dose) in several experimental models related to these kinds of psychopathological entities. In contrast, such and effect cannot be found in humans suffering from depressive symptoms, a chronic treatment for at least 3 weeks being necessary in order to obtain positive effects. Therefore, it is necessary to know the physiology of each animal to avoid distortions and mistaken generalizations.

  4. (4)

    Similarities in form of behavior (topography) do not mean similarities in biological basis. Whenever threatened, chimpanzees frequently exhibit a behavior of laughing [18]. The same topography is exhibited by humans, however, most of the time it is unrelated to a response toward a threatening stimulus. In our species, laughing often indicates an expression of joy. Thus, the ecology of an animal can favor similar behaviors, but with diverse functions and contexts.

  5. (5)

    Every scientific study points toward a central tendency for the studied phenomenon

    It is not possible to deduce that all organisms will have the very same reaction when exposed to a certain situation. It depends on the ecology, species, or even animals of the same species, but dwelling in different environments may show diverse responses related to learning history or even to inherited genes, expressed or silenced.

  6. (6)

    Be aware to the characteristics of the proposed method

    The same model can be proposed with procedural variations and will provoke changes on its meaning. A good example is given by the elevated plus-maze model. Some studies use this test to measure anxiety-like behaviors with only a single exposure of the animal to the apparatus. However, there are other studies using this test to measure fear, or for some, aversive learning, using a method in which the animals must undergo testing for two consecutive days with the same apparatus [19]. Therefore, understanding the method is essential for the study.

  7. (7)

    Review the concept of the studied psychopathology in addition of possible biases by the authors toward it.

    In general, the authors already refer to these aspects in the introduction. Read them carefully in order to identify elements that indicate whether the author partially supports a point of view (and the work seeks to confirm it), or whether the study is less biased. Taking such care can improve the use of data from animal research by the clinical professional.

Conclusion

It follows that knowledge of major issues that guide the work of the researcher, as well as their own research, can be useful to the clinical professional, to the extent that they can generate new possibilities for treatments. However, care must be taken with certain generalizations related to experimental studies, because not always the experimental and clinical settings share the same characteristics, and such factor can be determinate for a proper research of the phenomena to be studied.