Alvin Brodish

Age-Related Adaptation of Pituitary-Adrenocortical Responses to Stress

It has been reported that aged rats show impaired feedback regulatory control of pituitary adrenocorticotropic hormone release by adrenal glucocorticoids, yet, show no age-related deficit in eliciting an adrenocortical stress response when compared to younger animals. However, the effects of age on the capacity of the pituitary-adrenocortical system to adapt from an acute to a chronic stress situation have not been fully resolved. In the present study, groups of 6-month-old (young) and 22-month-old (old) F-344 rats were sacrificed at various times during the 1st (day 1) and 3rd (day 3) acute exposure to a two-way electric shock-escape stress procedure and subsequently during the 28th (day 28) and 56th (day 56) chronic exposure. Determinations of stress-induced corticosterone and adrenocorticotropic hormone responses indicated that: (1) adrenocortical responses were similar between young and old rats on the first stress exposure, whereas by the third stress session corticosterone responses were higher in young than in old rats; (2) attenuation of pituitary-adrenal responses to chronic stress was less in old compared to young rats, and (3) environmental factors may delay the development of age-related physiological alterations in the pituitary-adrenocortical system.

Age-Dependent Effects of Chronic Stress on ACTH and Corticosterone Responses to an Acute Novel Stress

Aging effects on the hypothalamic-pituitary-adrenocortical system have been studied primarily in the sedentary, environmentally deprived laboratory rat. Since it is known that chronic activation changes the responsiveness of the hypothalamic-pituitary-adrenocortical system, the present experiments were undertaken to determine whether age-related effects on this system would differ between sedentary and chronically stressed rats. Groups of 6- and 20-month-old F-344 rats were exposed to daily sessions of a 2-way shock-escape procedure over a 6-month period. When the rats were 12 (adult) and 26 months of age (old), pituitary-adrenocortical responses to an acute, novel stimulus were examined in young and old chronically stressed and age-matched control rats. Young and old control rats showed essentially the same corticosterone response to an acute motion stress. Chronic stress exposure increased the corticosterone response to the novel acute stressor in young but not in old rats. ACTH levels in response to acute stress were significantly reduced in old control rats compared to young control animals. Chronic stress did not change the ACTH acute stress response in young animals, whereas in old animals chronic stress elevated the ACTH responsiveness so that the old rats showed stress-induced ACTH levels that were comparable to the young animals. In conclusion, the effects of chronic stress on the function of the hypothalamic-pituitary-adrenocortical system are age-dependent, and environmental factors can significantly influence the progression of aging of the hypothalamic-pituitary-adrenal system.

Central but not peripheral opiate receptor blockade prolonged pituitary-adrenal responses to stress

Evidence from pharmacological studies suggest that opiate systems may serve either inhibitory or stimulatory functions on stress-induced responses of the hypothalamic-pituitary-adrenocortical (HPA) axis. The objective of these experiments was to determine whether these discrepant findings may result, in part, from differential effects of central or peripheral opiate receptor blockade on HPA axis responses. To this effect, groups of rats received injections of either saline, naltrexone (NHCl) or the quaternary analogue naltrexone methobromide (NMBr). The animals were then exposed to 30 min of a motion stressor and blood samples were obtained from each rat for analysis of ACTH, corticosterone, and prolactin. The data showed that resting and stress-induced levels of prolactin were decreased by NHCl only. Although neither drug affected the magnitude of the stress-induced ACTH and corticosterone responses, treatment with NHCl, but not NMBr, delayed the poststress decline of these responses. Hence, we concluded that central opiate mechanisms may be important for cessation of HPA axis activity, after exposure to stressful situations.

Neuronal damage in the rat retina after chronic stress

Long-term exposure to escapable foot shock has been used to determine if chronic stress influences neuronal cell death in the retina of albino and pigmented rats. Histopathologic and morphometric approaches analyzed changes in photoreceptors and neurons of the bipolar and ganglion cell layers of the retina. Albino Fischer rats when exposed to chronic stress for 4-8 h daily for 1 week to 6 months, developed severe retinal damage, as compared to unstressed control retinas, with reduction in photoreceptor and bipolar neurons, particularly in the superior central retina. The damage was observed in male and female rats, but males appeared to be more susceptible to the influence of stress than female animals. Ganglion cells were unaffected. Photoreceptor destruction did not occur in Long-Evans pigmented rats under identical experimental conditions. The results suggest that: input of the sensory stimulus, light, to the retina of stressed rats augmented neuronal damage and might be required for its initiation; and hormones and/or neurotransmitters associated with long-term chronic stress might be related to increased neuronal cell death in the mammalian retina.

Effects of acute and chronic stress on the neural retina of young, mid-age, and aged Fischer-344 rats

Male Fischer-344 rats at 5 (young), 11 (mid-age) and 18 (aged) months of age were exposed either to a single, 1-h period of acute stress, or to daily 4-h periods (chronic) of escapable footshock stress for 6 months, and subsequently allowed a one month interval without stress. The influence of age and exposure to stress on the neural retina was examined by histopathologic and morphometric methods. Age changes in the retina of unstressed control animals included reduction in the thickness of the outer nuclear layer (ONL; photoreceptor nuclei) and of the retina, especially in the peripheral areas. The superior hemisphere was more severely affected than the inferior retina. Exposure to acute stress did not influence retinal histopathology. However, in mid-age and aged rats exposed to chronic stress, the ONL and retinal thicknesses were reduced significantly. Our results indicate for the first time that exposure of rats to chronic stress produces changes in retinal morphology that are associated commonly with aging, such as extensive loss of peripheral photoreceptor cells. In addition, the results show that the effects of chronic stress exposure are greatest in aged rats. The effect of light exposure on the aging retina was not investigated since all rats were exposed to the same total photoperiod.

Impairment of immune function after cessation of long-term chronic stress

A pronounced impairment of mitogen-induced proliferation of splenic lymphocytes was observed in Fischer-344 male rats 1 month after termination of exposure of the animals to stress. The stress model used in these experiments was random schedules of a signaled, escapable electric foot-shock stress for 2-4 h/day over a period of 6 months. The magnitude of the observed immunosuppression correlated positively with the total, cumulative stress exposure received by the animals. The effect was not secondary to changes in the percentage of splenic T lymphocytes in stressed, compared to control rats. Also, at the time of sacrifice, plasma levels of corticosterone were comparable in experimental and control animals. Therefore, the immunosuppression observed 1 month after the last stress session cannot be attributed to pituitary-adrenocortical hyperactivity, at the time of sacrifice. These results provide the first evidence that stress-induced immunosuppression is not restricted to the period of exposure to the stress. This finding may contribute to a better understanding of the suggested association between stressful life events and increased susceptibility to disease in humans.

Effects on immune responses by chronic stress are modulated by aging

Male Fischer-344 rats at 5, 11, and 18 months of age were exposed to chronic stress for 6 months and subsequently allowed a 1-month interval with no stress before examination of splenic lymphocyte proliferative responses, IL-2 secretion by T cells, and NK cell activity in stressed and age- and sex-matched control animals. All four responses declined as a function of age in control rats. Stress exposure significantly decreased concanavalin A and lipopolysaccharide proliferative responses in 12- and 18-month-old compared to control rats without altering IL-2 secretory capacity. NK cell activity was slightly depressed by stress only in 18-month-old rats. By contrast, in 25-month-old animals that already demonstrated immune response levels lower than those of younger animals, stress did not significantly affect the responses examined. Thus, younger rats were more susceptible to a decline in host-defense responses induced by long-term chronic stress than older rats. Overall, the data suggest that aging significantly and differentially modulates the ability of environmental stress to influence the immunocompetent status of the organism.

Gender and chronic stress effects on the neural retina of young and mid-aged Fischer-344 rats

Young (5 months) and mid-aged (11 months) male and female Fischer rats were exposed to daily (5 days/week) chronic escapable foot-shock stress for 6 months. Following a subsequent 1-month rest period, by which time the animals were 12 and 18 months old, neural retinas were evaluated histopathologically and morphometrically. A significant reduction in the thickness of the retina occurred in the mid-aged, as compared to the young animals. A severe age-related loss in photoreceptor cells, particularly in the peripheral zones of the retina, occurred in a pattern resembling that described for aging humans. The effect of stress was to increase photoreceptor loss in a pattern resembling that of age-related cell loss. Stress-associated photoreceptor cell death was observed in males and females of both ages, but was more pronounced and statistically significant for mid-aged males (a five-fold increase in cell loss over females). The results demonstrated that exposure of rats to chronic escapable foot-shock stress exacerbates retinal changes commonly associated with aging and that the deleterious effects of chronic stress exposure were greater in the older age, male group.

Control of ACTH secretion by corticotropin-releasing factor(s).

Publisher Summary This chapter reviews the control of adrenocorticotropic hormone (ACTH) secretion by corticotropin-releasing factor (CRF). The synthesis and release of the hormones of the adenohypophysis are controlled by substances released from nerve endings in the hypothalamus and conveys to the anterior pituitary gland by the portal vessels. The evidence that demonstrates the fundamental importance of the hypothalamus and the hypothalamo-hypophysial portal vessels came primarily from experiments that involve pituitary stalk transection, transplantation of the pituitary gland to a site remote from the sella turcica, and selective destruction or stimulation of the hypothalamus. The realization that the hypothalamus contains substances capable of affecting pituitary activity attempts to isolate and identify these neurohormones. Several hypothalamic releasing hormones are isolated and their structures are determined. It is postulated that each pituitary hormone is controlled by a single hypothalamic hormone. Many aspects of Adrenocorticotropic hormone (ACTH) release are modulated by the central nervous system (CNS). Such regulation is mediated by a corticotropin-releasing factor. The production of CRF occurs within neurosecretory cells that share their secretory properties and the property of synaptic activation by neurotransmitter substances with other nerve cells.

Glucoregulatory responses of adult and aged rats after exposure to chronic stress

Stress has been implicated as an environmental factor that may accelerate the process of biological aging. However, this proposal has remained largely anecdotal due to relatively few studies that directly tested this hypothesis. In the present experiments groups of 6-month-old and 20-month-old male F-344 rats were chronically stressed for a six-month period. After the last stress session, when the animals were 12 months of age (adult) and 26 months of age (old), control and chronically stressed rats were tested for their ability to: (a) elicit glucose and insulin responses to an acute, novel stressor; (b) remove a circulatory glucose load elicited either by acute stress exposure or by injection of d-glucose; and (c) raise insulin levels after a glucose challenge. In control rats, we observed a deficit in each of these parameters in old compared to adult rats. Exposure to chronic stress did not exacerbate deterioration of these response mechanisms in either adult or old rats. In fact, the data showed a modest improvement in glucose tolerance in chronically stressed compared to age-matched control rats. We conclude that chronic stress did not exacerbate age-dependent decline of glucoregulatory capacity. From these results and from our earlier work, we speculate that the decline during aging of the functional integrity of systems involved in the response to stress may be sustained by periodic challenges from the organisms external environment.