**1. Introduction**

Despite approximately 100 years of intensive research (and more than 1 million citations in PubMed), stress, due to its multidimensional characteristics, remains a problematic concept not only in equine but also in human medicine; even today there is not a consensus on the question of what is stress? Stress may be defined as a relationship between an organism and external or internal factors that act to disrupt homeostasis. It has been suggested that "Living beings have evolved various specific and nespecidic reactions and pathways to mitigate the detrimental effects of stress to restore homeostasis" [1]. Thus, common acute stress responses can be evaluated as a process of constant flow moving around a homeostatic point, which is the optimal state for the existence of living beings (including horses). However, this definition also leads to a broader concept of stress, since it can include all temporary physiological adaptations to any change in

the environment. All living organisms, from the bacterium, to the horse or human, live (and lived) in potentially dangerous conditions, and in the process of evolution, they have developed specific protection mechanisms to survive before leaving offspring. There is not a consensus whether the highly variable stress environment promotes adaptation and the process of evolution itself, or only contributes to reflex defense [2]. In any case, stress responses in living organisms are constitutional—genetically programmed and are constantly modulated by environmental factors in the form of the gene–environment interactions [3, 4]. Thus, equine temperament traits (e.g., neophobic and neurotic behavior) that are known to be heritable strongly influence the intensity of the animal's stress response [4, 5]. Various specific equine genes influencing behavior have been identified [6]. For example, a frustration-related stress behavior in stabled horses is linked to an A–G substitution in the DRD4 (dopamine receptor) gene [7]. Additionally, it was found that an "A" variation of the G292A version of the DRD4 gene contributes to decreased curiosity and increased vigilance, and was more prevalent in Thoroughbreds compared with native breeds [8].

In the stress-induced disturbance of hemostasis or a possible threat to it, it is commonly noticed that a nonspecific multisystem three-stage body response occurs, which the famous Canadian endocrinologist Dr. Hans Selye (1907–1982) first termed the General Adaptation Syndrome (GAS) [9]. An alarm is the first stage or wave, where animals through a high concentration of catecholamines and activation primarily of cardiovascular, respiratory, and locomotory systems, and large energy consumption, trying to cope with adverse, threatening situations, or to escape from them ("fight-flight-or-freeze" response). In free nature, horses show usual a proactive response—flight (fearful behavior), rather than fight (or aggressive-dominant behavior), and this is considered a fundamental natural survival mechanism that increases protection in a threat environment. Logically, without this alarm phase developing through evolution, the horses would have no chance of escaping predators and ensuring their survival and continuation of the species. Occasionally, in "human controlled" environments, horses in the alarm phase show a passive response that involves behavioral inhibition, with lower locomotion, immobility, or withdrawal, but with focused attention. Which reaction horses show depends on the stress factors, and the reactivity of the neuroendocrine and sympathetic nervous systems. In this first wave of the stress response, within seconds there is an increased release of catecholamines, and it has been noticed that there is also increased secretion of corticotropin-releasing hormone (CRF), prolactin, growth hormone, and *glucagon, and a decrease in* the release of hypothalamic gonadotropin-releasing hormone (GnRH).

If the stressful situation is not resolved, the horse's body uses its additional energy resources and activates other physiological systems to protect or adapt to the stressful condition. This is the resistance stage. In this phase or the second wave, an increase in the concentration of glucocorticoids is mainly noticed. If the physiological compensatory mechanisms have succeeded in overcoming the stress, the recovery stage is entered. In contrast, if the animal body has used up its resources and is unable to maintain normal homeostasis that leads to the stage of exhaustion with various pathophysiological changes occurring.
