29,30 Normal versus pathological anxiety Although anxiety is a natural adaptive reaction, it can become pathological and interfere with the ability to cope successfully with various challenges and/or stressful events, and even alter body condition (eg, formation of gastric ulcers). In 1926, following a major flooding disaster in Leningrad, SIRT pathway Pavlov reported a state of “chronic inhibition” and learning impairment Inhibitors,research,lifescience,medical in the dogs that had been successfully trained for conditioned responses in his laboratory and had directly experienced the flood.31 This

observation (which may be one of the first laboratory-based accounts of the symptoms of posttraumatic Inhibitors,research,lifescience,medical stress disorder) and other experiments were the basis for his later studies on “experimental neuroses” in dogs. Pavlov discovered large differences in dogs’ individual susceptibility to psychopathology, and attributed these differences to “nervous types.” He described four types analogous to the four temperaments of Hippocrates, which, according to him, resulted from the combination of three factors: the “strength” of the nervous system (its degree of resistance

to excitation or inhibition), Inhibitors,research,lifescience,medical the equilibrium between excitation and inhibition processes, and the capacity to shift from inhibition to excitation and vice versa.32 Although Pavlov’s typology is outdated, it is now recognized that increased vulnerability to anxiety and its disorders is associated with particular

traits or endophenotypes, ie, traits that may be intermediate in the chain of causality from genes to disease.33 These traits may be innate or acquired during development or through experience. Barlow has defined three interacting sets Inhibitors,research,lifescience,medical of vulnerability Inhibitors,research,lifescience,medical factors for the development of human anxiety disorders in humans: (i) a generalized biological vulnerability, mainly of genetic origin; (ii) a generalized psychological vulnerability, resulting in particular from early life experiences; and (iii) a specific psychological vulnerability, focused on particular events or circumstances.16 The latter set is probably implicated in the development of unless specific anxiety disorders (as opposed to generalized anxiety disorders), ie, social phobia, obsessive-compulsive and panic disorders, and specific phobias. Increased anxiety in animal models, as a trait, can be attributed to at least two sets of factors: (i) a genetic predisposition, essentially linked to the expression of genes that are involved in the various neurochemical mechanisms underlying fear and anxiety; and (ii) the influence of environmental factors. These environmental factors can interact with the expression of the relevant genes during early development and determine the functional properties of the neural and biochemical systems involved in coping with stressful events.