Invited MinireviewSensitization associated with stressors and cytokine treatments
Introduction
Stressful events may elicit marked behavioral and neurochemical repercussions, depending on the characteristics of the stressor, various organismic variables (e.g., strain, age), and previous stressor experiences. Behaviorally, animals ordinarily engage in a variety of species-typical defensive strategies to attenuate or eliminate the impact of the stressors. This is coupled with a cascade of hormonal and neurotransmitter changes that are thought to influence the organisms ability to contend with a challenge. The increased neurochemical activity may serve a variety of adaptive functions, including regulation of inflammatory, immune, cardiovascular, metabolic, and reproductive processes (Sapolsky, Romero, & Munck, 2000). It is assumed that when neurochemical and behavioral coping processes are ineffective or overly taxed (allostatic load), vulnerability to behavioral and physical pathologies is increased (McEwen, 2000).
Of the various stress response systems, hypothalamic–pituitary–adrenal (HPA) functioning appears to be fundamental in dealing with a variety of different challenges. Stressors provoke the activation of neurons of the paraventricular nucleus (PVN) of the hypothalamus, resulting in the release of corticotropin releasing hormone (CRH) from the median eminence, which then stimulates ACTH secretion from the anterior pituitary, and hence adrenal glucocorticoids secretion. Glucocorticoids, the final product of the HPA response, have multiple functions, acting to either permit, stimulate, or suppress an ongoing stress response, or it may serve in a preparatory fashion to deal with anticipated stressors (Sapolsky et al., 2000).
While activation of this system plays a pivotal role in the management of stressors, neuronal activity in several limbic brain regions are also provoked by aversive stimuli, and may contribute to altered mood states. Stressors excite various amygdalar nuclei as well as the bed nucleus of the stria terminalis, which are involved in initial processing of fearful stimuli, the development of anxiety, and the subsequent generation of behavioral outputs to contend with the challenge. As well, stressors excite monoamine neurons within the medial prefrontal cortex (mPFC), which might function in an appraisal capacity, and dopamine (DA) neurons in the nucleus accumbens, which may serve to affect motivational processes, although it is clear that this site serves other functions as well (Davis & Whalen, 2001). Ultimately, the stress response reflects the coordinated activation of a wide range of central and peripheral processes. Whether stressors elicit pathology, as well as the nature of the pathology provoked, may be dependent on the particular system least able to adapt to the load imposed.
Section snippets
Sensitization associated with psychogenic and neurogenic stressors
Typically, the neurochemical changes provoked by stressors are fairly transient (measured in minutes or hours), again depending on the characteristics of the stressor and on various organismic factors (Anisman, Zalcman, & Zacharko, 1993). However, these neurochemical changes can subsequently be re-elicited by relatively mild stressor conditions that would otherwise have had only limited effects (Anisman et al., 1993). Such a stressor-provoked sensitization has been demonstrated with respect to
Cytokine-related sensitization effects
Psychogenic and neurogenic stressors have been thought of as “processive” stressors, as they involve appraisal of a situation (or stimulus), thus entailing higher order cortical processing. More recently, the conceptualization of stressors has been broadened to include “systemic” (e.g., metabolic) insults, such as bacterial or viral infection (Herman & Cullinan, 1997), particularly as they may induce many (but not necessarily all) of the neurochemical alterations ordinarily associated with
Mechanisms associated with sensitized corticoid responses
Multiple distinct processes, some of which involve different temporal profiles, appear to be operative in accounting for the sensitized responses elicited by TNF-α. One seems to involve central processes, and a second involves peripheral factors that may or may not have been related to immunological processes. As Tilders and his associates demonstrated with regard to IL-1β, we observed that over time following acute TNF-α administration, co-expression of AVP and CRH increased within the
Sensitization of central processes
Proinflammatory cytokines are known to affect monoamine functioning in several brain regions. For instance, in vivo analyses of monoamine release and/or analyses of postmortem tissue indicated that, when administered acutely, IL-1β increased the utilization of NE and/or serotonin (5-HT) (reflected by increased MHPG and 5-HIAA, accumulation) within the several stressor-sensitive regions, including the locus coeruleus, PVN, arcuate nucleus/median eminence, hippocampus, central amygdala, nucleus
Concluding remarks
Cytokines, like stressors, may promote wide-ranging variations of autonomic, neuroendocrine, and central neurotransmitter activity, including increased HPA neuroendocrine functioning and variations of monoamine activity. Moreover, both cytokine and stressor treatments have pronounced proactive effects, so that later re-exposure to the challenge may provoke an augmented response. It appears that multiple systems are subject to such a sensitization, characterized by diverse temporal profiles and
Acknowledgments
Supported by the Canadian Institutes of Health research. H.A. holds a Canada Research Chair in Neuroscience, and is an Ontario Mental Health Foundation Senior Research Fellow.
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