Modelos animales para el estudio de la ansiedad: una aporximación crítica

• Claudia Gómez ^[1] ; José Alfredo Saldívar González ^[1] ; Rodolfo Rodríguez ^[1]
  1. [1] Departamento de Farmacología, Facultad de Medicina, UNAM
• Localización: Salud mental, ISSN 0185-3325, Vol. 25, Nº. 1, 2002, págs. 14-24
• Idioma: español
• Enlaces
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• Dialnet Métricas: 4 Citas
• Resumen
  • español

    La evidencia generada en los últimos años parece señalar claramente que la estructura y la actividad cerebral se encuentran evolutivamente vinculadas en diferentes especies. La relación establecida durante el proceso evolutivo entre las diferentes especies de mamíferos permite estudiar algunas funciones mentales superiores humanas, normales y patológicas, en los animales. Este precepto fundamental ha proporcionado el sustrato teórico para la introducción del método experimental en psiquiatría. La intención de reproducir elementos de padecimientos psiquiátricos en animales constituye un capítulo con identidad propia, hoy en día incuestionable en el ámbito de la investigación médico-biológica.

    Se estima que la investigación preclínica en el área de la ansiedad utiliza cerca de 30 modelos animales que permiten observar y cuantificar conductas de diversa índole. Estas conductas responden de una manera específica al tratamiento con compuestos ansiolíticos o ansiogénicos. Entre éstos, los modelos condicionados involucran procedimientos de castigo o conflicto, generalmente un choque eléctrico. En este caso un animal entrenado para emitir o suprimir una respuesta, modifica el patrón de ésta al ser tratado con un fármaco.

    Este grupo de paradigmas permite al experimentador controlar los niveles de conducta basal, pero requiere de una fase de entrenamiento, además de exigir análisis minuciosos con objeto de descartar los efectos putativos inespecíficos, no relacionados con el tratamiento sino con el aprendizaje, la memoria, la ingesta de agua y alimento, y las funciones senso-motrices y perceptuales.

    Hay otro gran grupo de modelos animales que, en contraste con las pruebas de respuestas condicionadas, estudia conductas no condicionadas. Este grupo de modelos se ha desarrollado mediante la identificación y clasificación del repertorio conductual natural de diferentes especies animales. Aunque este tipo de modelos presenta mayor variabilidad que los paradigmas basados en respuestas condicionadas, numerosos autores atribuyen a los modelos no condicionados un nivel más alto de validez neurobiológica, no requieren entrenamiento y son menos susceptibles a la interferencia de procesos mnemónicos o motivacionales. Sin embargo, persiste una discrepancia importante entre la ansiedad según el DSM IV y los modelos animales usados.

    La mayoría de los modelos adolece de puntos de referencia onto y filogenéticos comunes entre el padecimiento y éstos. En la actualidad, se considera que los trastornos de la ansiedad constituyen perturbaciones de respuestas de defensa como la hipervigilancia, y reacciones de evitación y escape que reflejan un fenómeno adaptativo normal. En conclusión, la validez en el uso de los modelos animales para el estudio de la ansiedad depende de la aceptación de que tanto la ansiedad normal como la patológica, incluyan sustratos anatómicos y neuroquímicos comunes y, que éstos, a su vez, se relacionen con sistemas neurales involucrados en las reacciones defensivas de las especies.

  • English

    Recent evidence suggests that function and brain structure are evolutionary related in several species. This historical relationship between different mammal species allows the study of higher human mental functions in animals under normal and pathological conditions. This idea constitutes theoretical support for the application of the experimental method in Psychiatry. The modeling of psychiatric illness in animals represents today an important chapter of medical and biological research conceptually supported by the above-described ideas. The introduction into the clinic of the chlorpromazine, an aliphatic phenotiazine, at the beginning of the 50´s. resulted in a turning point in the development of experimental psychiatry. This fact was essential for the introduction of the experimental approach. Artificial or natural development of psychosis in humans could be observed under different medical conditions such as neurosyphilis, endocrinopathies; hypo and/or hyperthyroidism, head trauma, alcoholism and heavy metal intoxication (arsenicum, plumbium, and cadmium). At the end of the 40´s Hoffman synthesized a compound able to strong disorganize a human or animal behavior, the lysergic diethialamide acid “LSD” even at very low doses.

    Nevertheless, the possibility of pharmacological correction of psychotic symptoms represented the real core for a radical change in the understanding of the neurological basis of higher mental function disturbances. This paradigmatic change could not occur in the absence of a pharmacological treatment of psychotic symptoms. Based on this line of thinking, researchers started to model mental illnesses (other than psychosis disturbances), using laboratory animals. The simulation of psychiatric illnesses was mainly oriented toward their pharmacological correction. This approach ignored the aethiopathological factors, focusing the efforts in the reduction of clinical symptoms. In addition, the lack of a conceptual body on the neurobiological basis of mental illness and the lack of adequate instruments for its research delayed the development of the scientific basis for clinical psychiatry. Nowadays, the chapter of anxiety disorders besides clinical classification includes animal research in most psychiatric areas. Preclinical approaches for the study of anxiety include more than 30 different animal models. These paradigms study behaviors that in a particular way are modified by anxiolytic or anxiogenic compounds; among them are the conditioning animal models based on punishment or conflict procedures. These experimental designs are founded on the assumption that laboratory animals modify their pattern of response when conditioned aversive and unconditioned stimuli are temporarily associated, eliciting operant or classical responses. Most of these designs inhibit animal response when aversive and unconditioned stimuli are paired. The classical dogma of such an approach assumes that well-known anxiolytic compounds (barbiturate, benzodiazepines), frequently used as gold standard compounds, decrease behavioral inhibition in trained individuals. Generally the aversive stimuli used is a low electrical shock. Thus, an animal trained to perform a particular response modifies it after treatment with a known (gold standard) or unknown (the testing molecule) compound. An interesting point of these models is their similarity with generalized anxiety i.e., the real aversive stimulus is absent when the experiment is carried out, a fact that resembles one of the conditions of anxiety in the clinic. This feature makes these models different from those based on fear-elicited responses, paradigms that model simple phobias. Conditioning experimental models allow the control of basal behavioral levels, however the animals require training previously to the experimental session. In addition, detailed analyses are necessary to discriminate non-specific effects of drugs on learning, memory, motor, perception food and water consumption.

    Several authors consider these features as diminishing the construct validity of the conditioning models, arguing the involvement of artificial elements, unrelated with emotional stress in animals in wild conditions and different of clinical anxiety. Other important tests used for the study of anxiety evaluate unconditioned responses. These models are supported on the species memory, i.e., analyze the innate behaviors of naive animals. These groups of behaviors are observed each and every time the subjects encounter the same stressful situation, not necessarily associated with painful or electrical stimuli. Many researchers believe that these models offer higher level of neurological validity. However, a strong level of intraspecific variability compared with those based on conditioned responses has been found. Unconditioned models are less dependent on the memory or motivational processes.

    There is an important discrepancy between DSM IV anxiety inventory and the animal models used. This discrepancy is related to the lack of phylogenetic relationships between the illness and the models. This concept suggests that some human behaviors considered as disrupting responses represent the cultural expression of archaical pre-human behavior, such as hipervigilance, defensive avoidance and escape responses, adaptive in natural conditions, but disadaptive in some cases in human groups. The validity of the animal models for the study of anxiety depends on the consensus that normal and/or pathological anxiety has anatomic and neurochemical substrates that interact in the neural systems involved in the defensive species reactions. The participation of different brain areas regulating, unlike in nature forms of anxiety has been recently proposed. Before this notion, the unified theory of limbic system regulation of the emotional activity was generally accepted. In summary, based on the above-described ideas it seems that there is not one single animal model for the study of anxiety. Different tests reflect at least one specific feature of the anxiety disorder and it must be carefully chosen