John E. Ottenweller

Plasma corticosterone levels during repeated presentation of two intensities of restraint stress: Chronic stress and habituation

This study measured plasma corticosterone levels in male rats during repeated daily presentations of two intensities of restraint stress. The corticosterone response to a stress session was defined as the change from pre-stress levels to levels after 60 minutes of restraint. With the relatively intense stress imposed by four limb prone restraint, the corticosterone response partially habituated over seven days due to increasing basal corticosterone levels. However, even on day 7, there was still a large corticosterone response. With the milder stress of immobilization in a tube, the corticosterone response did not habituate at all over 21 days of repeated stress despite rising basal levels. Stress levels of corticosterone did not show significant change over days in either of the two restraint groups. Further, rising basal corticosterone levels suggest that repeated restraint produced a chronic stress state in these rats which may vary in some qualitative way with stressor intensity. Control rats placed in the same room as the stressed rats during the two stresses initially had increased corticosterone levels that matched the levels achieved in the stressed rats. The responses in control rats for the intense stress did not habituate completely in 7 days, whereas those in the control rats for the mild stress habituated completely within 3 days. These data suggest intraspecific communication of the intensity of stress.

Dobutamine digital echocardiography for detecting coronary artery disease

To assess the value of dobutamine echocardiography for detecting coronary artery disease (CAD), 70 men (mean age 62 +/- 8 years) presenting for coronary angiography were prospectively studied. Dobutamine (2.5 to 40 micrograms/kg/min) was infused in 3-minute stages. Digital echocardiograms were recorded on-line at baseline, during low- and high-dose dobutamine infusion, and at recovery. An echocardiogram positive for CAD was defined as one showing a new wall motion abnormality induced by dobutamine. Compared with coronary angiography, the overall sensitivity of dobutamine echocardiography for detecting CAD was 86%, specificity 95% and accuracy 89%. The sensitivity for detecting 3-vessel CAD was 100%, 89% for 2-vessel and 69% for 1-vessel CAD. The accuracy of predicting multivessel disease by 2 methods was 71% and 84%, respectively. Heart rate at the echocardiographic ischemic threshold was lower in patients with 3- and 2-vessel CAD versus 1-vessel CAD (89 +/- 17, 95 +/- 18 and 118 +/- 18 beats/min, respectively, p less than 0.01); rate-pressure product was also lower in patients with 3- and 2-vessel CAD versus 1-vessel CAD (12.7 +/- 3.6, 13.7 +/- 2.8 and 18.9 +/- 44 x 10(3) beats/min x mm Hg, respectively, p less than 0.01). Heart rate was the most important physiologic determinant of ischemia induced by dobutamine. There were no major complications during the study. Thus, dobutamine digital echocardiography is an excellent test for identifying CAD and should be beneficial in patients unable to exercise.

Effect of stressor intensity on habituation of the adrenocortical stress response

Although it is known that the number of presentations of a stressor can influence the adrenocortical stress response, relatively little information exists on how stressor intensity affects this process. To evaluate this, we repeatedly presented rats with stressors of 3 different intensities and sampled blood for corticosterone. The first major finding was that the rats initial adrenocortical responsiveness regardless of the stressor employed was a critical variable. Rats that showed a small corticosterone response showed no evidence of habituation or of differences due to stressor intensity. Rats that showed an initial robust response all showed partial habituation of their corticosterone response over time but the patterns varied with stressor intensity. Handled and prone restrained rats showed the same pattern but rats subjected to the more intense stressor of supine restraint showed delay in habituation and tonically elevated responses. These data indicate that individual differences in reactivity to stressors as well as stressor intensity can influence the pattern of the stress response over the course of repeated administration of the stressor.

Adrenocortical and behavioral responses to repeated stressors: toward an animal model of chronic stress and stress-related mental illness

Research in chronic stress has been hampered by the absence of an operational definition for that condition. To explore possible criteria for chronic stress, we repeatedly exposed rats to 2 hr of tail shock per day. After several days, we found elevated prestress corticosterone levels and abnormal behavior, including decreased food consumption, fear-like suppression of activity immediately before stress, greater hesitancy to drop from a suspended wire, and decreased exploratory behavior in a novel environment. A less intensely stressed group of rats also had elevated prestress corticosterone levels, but not the abnormal behaviors that persisted in shocked rats after the stress sessions were discontinued. We propose that abnormalities in both adrenocortical function and behavior are a better marker for chronic stress than abnormalities in either of these systems alone. The animal model we have described may be useful for studying factors that contribute to development of chronic stress or PTSD.

Delayed startle sensitization distinguishes rats exposed to one or three stress sessions: Further evidence toward an animal model of PTSD

Posttraumatic stress disorder (PTSD) may occur in humans exposed chronically to stressors or after a single exposure to a traumatic event. A distinguishing feature of patients with PTSD is an exaggerated startle response, evident long after the traumatic event. We have observed similar abnormalities in our animal model of a chronic stress state. Rats exposed to 3 days (3DS) of our stress regimen (2-hr sessions of 40, 2 mA tailshocks) have exhibited a consistent pattern of persistent physiological and behavioral abnormalities including an exaggerated startle response several days after stressor cessation. In contrast, rats exposed to a single stress session (1DS) have exhibited many, but not all, of the persistent abnormalities displayed by 3DS rats. The present experiment compared the startle responding of 3DS and 1DS rats 4, 7, and 10 days after stressor cessation. Consistent with previous work, stressed rats exhibited elevated basal plasma corticosterone (CORT) levels the first day poststressor. These CORT levels were sensitive to the number of stressor exposures with higher CORT levels in 3DS rats than in 1DS rats. As for startle responding, the 1DS rats exhibited an exaggerated startle response 7 days poststressor, whereas startle sensitization was apparent 10 days poststressor in 3DS rats. Thus, the appearance of an exaggerated startle response after stressor cessation appears to be related to the number of stress session exposures. These animal models, the 3DS and 1DS rats, may be useful to gain insight into the neurobehavioral changes associated with PTSD.

Adrenal hormonal indices of stress in laboratory rats

When individual rats were exposed to different intensities of a stressor, foot shock, plasma catecholamines were found to be sensitive and reliable indices of the stress. Plasma corticosterone did not perform as well. Similarly, levels of both plasma epinephrine and norepinephrine correlated highly significantly with a behavioral measure of the degree of stress--namely, the amount of movement about the cage seen during the 30 sec shock period. Importantly, this behavioral measure was as sensitive and reliable an index of stress as the catecholamines. However, use of either the catecholamines or this behavioral measure as a clinically useful measure of the level of stress was limited by the fact that their responses to the stressor were extremely short-lived. Nonetheless, because the catecholamines reliably and sensitively track the intensity of a stressor, they appear to be a good visceral measure of stress, perhaps the best currently available. But the behavioral concomitants of stress are quickly and easily quantifiable and present a wide range to study, starting with alerting, through a progression of more aroused motor activity, and ending with fight-flight. Because the behavioral concomitants of stress have not been as intensively studied as the endocrine ones, we believe that future efforts to find a clinically useful index of stress will be rewarded by a refocussing of attention away from the visceral respondent to the overt behavioral one.

Effect of stressor intensity on habituation and sensitization of glucocorticoid responses in rats

This experiment was designed to study the effect of stressor intensity on habituation/sensitization of the adrenocortical stress response in rats. Rats were given 18 shocks in 3-hr daily sessions for 8 days, and a single shock probe before the sessions was used to determine how adrenocortical responsiveness changed with repeated exposure to the stress sessions. When lower intensity shock was given, the changes in plasma corticosterone response to shock probes followed a U-shaped curve--with a response that first habituated to no-shock control levels but later returned to the same magnitude as seen on the 1st probe day. Plasma corticosterone responses in rats given higher intensity shock never habituated and instead demonstrated an increased response indicative of sensitization; a temporal delay of 1 week occurred before sensitization developed. Responsiveness to exogenous adrenocorticotropin 24 hr after the last stress session was monotonically related to the intensity of the stressor presented during the experimental sessions. These data are consistent with the rule from the habituation literature that stimulus intensity is inversely related to the magnitude of habituation. Thus the data extend the dual process theory of Groves and Thompson (1970) to an endocrine respondent. The data also suggest that an explanation as to discrepancies in the literature concerning adrenocortical response to repeated presentation of stressors may relate to differences in the stressor parameters used.

A chronic stress state in rats: Effects of repeated stress on basal corticosterone and behavior ☆

The chronic stress state has previously been defined as persistent visceral arousal coupled with behavioral abnormalities. To determine the number of stressor exposures necessary to induce a chronic stress state, male rats were given 2 hours of inescapable shock on 10, 7, 4, or 3 consecutive days. The 3-day stress group had the most pervasive changes in the variables measured: persistently elevated basal plasma corticosterone (CORT), continued weight loss in the post-stressor period, and abnormal behavior. More exposures to the stress regimen did not produce higher CORT levels or greater behavioral changes. Acutely stressed rats, exposed to 1 day of inescapable shock, had persistent CORT elevations without the other changes seen in the 3-day stress group. The data suggest that 3 days of our stress regimen are sufficient to produce a state of chronic stress and that some signs of this state begin to appear as early as the first exposure to our inescapable stress regimen.

Health Effects of a Mixture of Indoor Air Volatile Organics, Their Ozone Oxidation Products, and Stress

In our present study we tested the health effects among women of controlled exposures to volatile organic compounds (VOCs), with and without ozone (O3), and psychological stress. Each subject was exposed to the following three conditions at 1-week intervals (within-subject factor): VOCs (26 mg/m3), VOCs + O3 (26 mg/m3 + 40 ppb), and ambient air with a 1-min spike of VOCs (2.5 mg/m3). As a between-subjects factor, half the subjects were randomly assigned to perform a stressor. Subjects were 130 healthy women (mean age, 27.2 years; mean education, 15.2 years). Health effects measured before, during, and after each 140-min exposure included symptoms, neurobehavioral performance, salivary cortisol, and lung function. Mixing VOCs with O3 was shown to produce irritating compounds including aldehydes, hydrogen peroxide, organic acids, secondary organic aerosols, and ultrafine particles (particulate matter with aerodynamic diameter < 0.1 μm). Exposure to VOCs with and without O3 did not result in significant subjective or objective health effects. Psychological stress significantly increased salivary cortisol and symptoms of anxiety regardless of exposure condition. Neither lung function nor neurobehavioral performance was compromised by exposure to VOCs or VOCs + O3. Although numerous epidemiologic studies suggest that symptoms are significantly increased among workers in buildings with poor ventilation and mixtures of VOCs, our acute exposure study was not consistent with these epidemiologic findings. Stress appears to be a more significant factor than chemical exposures in affecting some of the health end points measured in our present study.

Persistent stress-induced sensitization of adrenocortical and startle responses

We assessed the functional adrenocortical and behavioral state of rats previously exposed to repeated stressor presentations. In Experiment 1, the whole-body startle response to threshold (91 dB) and suprathreshold (96 dB) stimuli was assessed in rats given 3 daily sessions (3DS) of 40, 2-mA tailshocks. The 3DS rats showed an exaggerated startle response to the threshold auditory stimulus 4 days poststressor compared to nonshocked controls (CON). An exaggerated startle response in stressed rats was not evident either 1 day or 10 days poststressor. In Experiment 2, adrenocortical sensitization and behavioral reactivity were assessed in rats exposed to 1 day (1DS) or 3 days of our stress regimen. Stressed rats exhibited elevated basal plasma corticosterone (CORT) levels 1 day poststressor which recovered by 9 days poststressor. Stressed rats also exhibited suppressed open-field activity 4 days poststressor. On the 10th day poststressor, rats were exposed to a single tailshock. The 1DS and 3DS rats showed both a sensitized and prolonged CORT response to stressor reexposure compared to control rats which received only the single tailshock. In addition, on the 11th day poststressor 3DS rats exhibited a moderate recapitulation of the elevated basal CORT levels seen after the initial stressor exposures. Thus, exposure to our stress regimen produces a chronic stress state in rats characterized by persistent behavioral and adrenocortical sensitization, as well as suppressed open-field activity and elevated basal CORT levels. Rats exhibiting a chronic stress state may be appropriate as a model for the study of stress-related psychophysiological illnesses, such as posttraumatic stress disorder.