Stressors encountered by humans may comprise major insults ranging from the loss of loved ones, unexpected calamities (hurricane, tornado, flood, war, accident), and financial distress, or they may involve a series of day-to-day annoying experiences. Both the severe and less intrusive stressors may influence physiological and behavioral processes, and both have been implicated in the provocation or exacerbation of a large number of illnesses, including the classical psychosomatic disorders and depressive illness, cardiovascular disease, as well as those that involve immune dysfunction.
The stress response has been considered as the homeo-static or adaptive biological and/or behavioral response (al-lostasis) to a stimulus that is appraised as being aversive. In general, stressors elicit behavioral responses to attenuate the challenge, and concurrently peripheral and central nervous system neurochemical alterations occur that may be of adaptive significance. Among other things, they may be essential in order that animals be prepared to respond appropriately to impending as well as ongoing stressors. Moreover, these biological changes may be necessary for the organism to react with appropriate emotional and behavioral responses, initiate and maintain effective defensive strategies, initiate processes that will protect the organism from pathogenic stimuli, limit overreaction of other neuro-chemical systems that might themselves lead to pathology, and minimize the physical and psychological impact of the aversive stimuli.
One of the fundamental, and most frequently examined, physiological responses elicited by stressors is the activation of the hypothalamic-pituitary-adrenal (HPA) axis. This system is readily stimulated not only by psychological or physical stressors but also by systemic stressors (e.g., immune activation), although they may do so by activation of a different neural circuit. Ordinarily, when a stressor is encountered, the paraventricular nucleus of the hypothalamus is activated, giving rise to the release of corticotropin-releasing hormone (CRH) from terminals located at the median eminence. This hormone stimulates the anterior pituitary, promoting the release of ACTH into circulation, which in turn stimulates the release of cortisol (or cortico-sterone) from the adrenal cortex. Cortisol is thought to play an integral role in facilitating adequate responses to stressful events and may serve to prevent overshoot of immune reactions.
It would be most adaptive for certain neurochemical responses to be mounted rapidly, regardless of the psychological attributes of the stressors (e.g., controllable vs. uncontrollable; predictable vs. unpredictable). Those systems that are necessary for immediate responses to contend with stressors (e.g., activation of the sympathetic nervous system), and even fundamental immune responses that act against pathogenic stimuli, should react comparably to both controllable and uncontrollable stressors. In contrast, those central systems that are uniquely involved in the appraisal of stressors would be influenced by the psychological attributes of the stressor. It is well known, for instance, that uncontrollable stressors provoke behavioral disturbances (reminiscent of depressive states) that are not as readily induced by controllable stressors. Some investigators have interpreted these differences as reflecting learned helplessness provoked as animals learn that they have no control over their environment. Others, however, have attributed the behavioral disturbances to the neurochemical alterations that may be unique to uncontrollable aversive events. Generally, stressors promote increased utilization and synthesis of neurotransmitters within particular regions of the brain. These include norepinephrine (NE), dopamine (DA), serotonin (5-HT), acetylcholine (ACh), GABA, and various peptides. Under conditions where behavioral control over the stressor is unavailable, greater strain is placed on neuronal systems, and consequently they may become overly taxed. The excessive utilization of neurotransmitters (or the decline of the transmitter secondary to excessive utilization) in certain brain regions may result in a net decline of the transmitter, thus leading to greater vulnerability to pathological states.
In addition to the immediate effects, stressful events may proactively influence the response to later stressor experiences. It seems that stressors may result in the sensitization of processes that promote central neurochemical functioning so that reexposure to the same stressor (and even to alternate stressors) at a later time may result in the neurochemical changes occurring more readily. Thus, such sensitization processes may contribute to the induction of stressor-related illnesses even at lengthy intervals following a trauma and may be responsible for the high rates of relapse associated with illnesses such as depression. It is important to note that in addition to simple sensitization effects, cross-sensitization has been observed so that stressors increase the response to drugs such as amphetamine and cocaine. Likewise, it has been shown that the administration of cytokines, signaling molecules of the immune system, may result in a sensitization effect so that the response is vastly increased on their reexposure. Thus, in considering the impact of stressors, one should consider not only the immediate repercussions but also the increased vulnerability that develops to later stressor experiences. It is also important to note that the sensitization grows with the passage of time and hence may be a contributing factor to illnesses that likewise appear to be linked to temporal processes (e.g., posttraumatic stress disorder).
The proactive effects of stressors are particularly notable among animals that had encountered distress early in life. For instance, studies in animals have shown that when pups are separated from the mother for several hours a day during early postnatal development, the adult response to stressors is particularly pronounced. In contrast, those animals that received early life stimulation (particularly those that received frequent licking and grooming) tended, as adults, to be more resilient to the impact of stressors.
Intuitively, one would imagine that the behavioral and neurochemical impact of acute stressors would be exacerbated with repeated stressor experiences. In fact, however, following chronic stressor regimens, some of the behavioral disturbances ordinarily provoked in rats and mice may be attenuated. This sort of adaptation is not limited to the behavioral effects of stressors but has been reported also with respect to physiological processes, including neurochemical and immunological functioning. For instance, the NE reductions ordinarily observed after acute stressors may be absent following protracted or repeated insults owing to a compensatory increase in the synthesis of the transmitter. As the stressor experience continues, however, the wear and tear on the system may become excessive (allostatic load) and may lead to increased vulnerability to pathological outcomes. It is thought that under such conditions vulnerability is increased with respect to mood, neurodegen-erative, and immunologically related disorders.
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