Acute and chronic stress effects on open field activity in the rat: Implications for a model of depression

To investigate the role of gonadal steroids in the hypothalamic-pituitary-adrenal (HPA) response to stress, we studied adrenocorticotrophin (ACTH) and corticosterone (B) responses to 20-min restraint stress in cycling female rats, and in ovariectomized (OVX) rats replaced with physiological levels of estradiol (E2) and progesterone (P). In cycling rats, we found significantly higher peak ACTH (P less than 0.01) and B (P less than 0.05) responses to stress during proestrus compared to the estrous and diestrous phases. No differences were found in either basal ACTH and B levels across the cycle phases. In a separate study, OVX rats were maintained on low, physiological levels of E2 and P with silastic implants for 3 days, and injected either with oil (O'), 10 micrograms of E2 (E') 24 h before stress testing, or with E2 and 500 micrograms P 24 and 4 h, respectively, prior to stress (EP'). These treatments mimicked endogenous profiles of E2 and P occurring during diestrous, proestrous, and late proestrous-early estrous phases, respectively. In response to stress, ACTH levels were higher (P less than 0.01) in the E' group compared to the EP' and O' groups. Although the peak B response was similar in all groups, the E' and EP' groups secreted more B after the termination of stress than did the O' group. Within the 20 min stress period, ACTH levels in the E' group were significantly (P less than 0.05) higher at 5, 10, and 15 min after the onset of stress, compared to the EP' and O' groups. Plasma B levels were significantly higher in the E' group at 5 and 10 min (P less than 0.05 and P less than 0.01, respectively) compared to the EP' and O' group. beta-endorphin-like immunoreactive responses to restraint stress were also significantly higher in the E' group compared to the EP' (P less than 0.05) and O' (P less than 0.01) groups. In contrast to the effect seen at 24 h, ACTH responses to stress 48 h after E2 injection in the E' group were comparable to O' animals. There was no effect of E2 on ACTH clearance, whereas B clearance was enhanced in E' treated animals vs. O'-treated animals. These results indicate that the HPA axis in the female rat is most sensitive to stress during proestrous. Such enhanced HPA responses to stress are limited to the early portion of proestrous, as progesterone appears to inhibit the facilitatory effects of estrogen on ACTH release during stress. Taken together, these results suggest an ovarian influence on both activational and inhibitory components of HPA activity.

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Variations in the Hypothalamic-Pituitary-Adrenal Response to Stress during the Estrous Cycle in the Rat

The hypothalamic-pituitary-adrenal (HPA) axis is one of the physiological systems involved in coping with stressors. There are functional shifts in the HPA axis and its regulation by sex hormones over the lifespan that allow the animal to meet the challenges of the internal and external environment that are specific to each stage of development. Sex differences in HPA function emerge over adolescence, a phenomenon reflecting the concomitant initiation of regulatory effects of sex hormones. The focus of this review is recent research on differences between adolescents and adults in HPA function and the enduring effects of exposure to stressors in adolescence. During adolescence, HPA function is characterized by a prolonged activation in response to stressors compared to adulthood, which may render ongoing development of the brain vulnerable. Although research has been scarce, there is a growing evidence that exposure to stressors in adolescence may alter behavioural responses to drugs and cognitive performance in adulthood. However, the effects reported appear to be stressor-specific and sex-specific. Such research may contribute toward understanding the increased risk for drug abuse and psychopathology that occurs over adolescence in people.

HPA function in adolescence: role of sex hormones in its regulation and the enduring consequences of exposure to stressors.

The hypothalamic-pituitary-adrenal (HPA) axis is a major component of the systems that respond to stress, by coordinating the neuroendocrine and autonomic responses. Tightly controlled regulation of HPA responses is critical for maintaining mental and physical health, as hyper- and hypo-activity have been linked to disease states. A long history of research has revealed sex differences in numerous components of the HPA stress system and its responses, which may partially form the basis for sex disparities in disease development. Despite this, many studies use male subjects exclusively, while fewer reports involve females or provide direct sex comparisons. The purpose of this article is to present sex comparisons in the functional and molecular aspects of the HPA axis, through various phases of activity, including basal, acute stress, and chronic stress conditions. The HPA axis in females initiates more rapidly and produces a greater output of stress hormones. This review focuses on the interactions between the gonadal hormone system and the HPA axis as the key mediators of these sex differences, whereby androgens increase and estrogens decrease HPA activity in adulthood. In addition to the effects of gonadal hormones on the adult response, morphological impacts of hormone exposure during development are also involved in mediating sex differences. Additional systems impinging on the HPA axis that contribute to sex differences include the monoamine neurotransmitters norepinephrine and serotonin. Diverse signals originating from the brain and periphery are integrated to determine the level of HPA axis activity, and these signals are, in many cases, sex-specific.

Barbara M. White

Papers

Plasma glucocorticoid elevation and desynchronization of the estrous cycle following unpredictable stress in the rat.