The Validity of Stress Models in Predicting Human Psychopathology: Behavioral and Neurochemical Correlates, and Targets for Pharmacological Evaluations

The inadequacy of the germ and terrain theories as the sole determinants of diseases led to the postulation that chronic stress plays a key role in the genesis and progression of many chronic human diseases through induction of a cascade of multi-systemic physiological dysregulations. The pathomechanisms underlying chronic stress-induced diseases include over-production of injurious chemical mediators, depletion of stress-protective molecules and inability to stimulate specific stress-protective pathways resulting from hypothalamic-pituitary-adrenal (HPA) axis activation. Molecular studies have also implicated myriads of epigenetic mechanisms that underlie dysregulation of genes in the neural circuitries in chronic stress-induced disorders. Generally, animal models are used as proxies for humans to elucidate the occurrence and progression of pathological processes, and development of pharmacological agents. Animal models of stress are widely used to investigate the neural, behavioral and biochemical mechanisms involved in chronic stress-induced psychopathology including depression, anxiety, posttraumatic stress disorders, schizophrenia, cognitive deficits, aggressive and addictive disorders. The purpose of the models is to correlate the physiological and behavioral changes associated with specific stressors to the etiology of diseases and responses to pharmacological treatments. Notably, animal stress models have predictive validity, face validity and construct validity attesting to their reliability in studying the pathogenesis of psychiatric disorders and pharmacological interventions. Broadly, they can be classified into predictable stress models and unpredictable chronic mild stress paradigm. Predictable stress models involve exposure of the organisms to a single stressor, which can lead to the development of tolerance, plasticity and adaptation upon repeated exposures. On the other hand, the unpredictable chronic mild stress paradigm that closely mimics how humans encounter different stressors on daily basis entails the exposures of the animals to multiple stressors, in a random manner; and it is now widely recognized as a valuable tool to elucidate the neurobiology of chronic stress-induced psychiatric disorders. This discourse aims to stimulate more robust studies on the neurobiology of chronic stress-induced psychopathologies, highlight some targets for pharmacological interventions, and the possibility of developing animal model(s) for testing social supports benefits in the face of adversity.