Depressive behavior and stress ulcer in Wistar Kyoto rats

229

J Physiology (1993) 87, 229-238 © Elsevier, Paris

Depressive behavior and stress ulcer in Wistar Kyoto rats W P P a r 6 a, E R e d e i b "VA Medical Center, Perry Point, Maryland 21902; bDepartment of Psychiatry, University of Pennsyh, ania, Philadelphia, Pennsyh,ania, USA (Received 19 April 1993; accepted 2 May 1993)

S u m m a r y - Wistar Kyoto (WKY) rats, as compared to several other rat strains, are hypoactive in the open field test and in the defensive burying test. WKY rats readily acquire a learned helplessness task as well as a passive avoidance tasks. WKY rats also reveal a greater susceptibility to restraint-induced stress ulcer. The behavioral tests suggest the presence of depressive behavior in WKY rats. When exposed to the Porsolt forced-swim test of 'behavioral despair'. WKY rats are judged as exhibiting more depressive behavior. Desipramine not only reduced immobility in the forced-swim test, but also diminished the severity of restraint-induced stress ulcer. These data suggested a heightened activity of the hypothalamicpituitary axis. Basal plasma ACTH levels did not differ between WKY rats and Wistar rats, but serial plasma ACTH response to restraint stress was significantly greater for WKY rats. These data suggest that depressive behavior is a characteristic of WKY rats and this strain is a valuable model for studying depression which may be induced by an exaggerated stress response. stress I depression I ulcer I Wistar Kyoto rat I ACTH

Introduction Behavioral scientists are fascinated with the possibility that psychological perturbations ('stressors') can influence the disease process. Gastric ulcer of the stomach has often been considered a classic example of psychosomatic disease. This belief received considerable support from Selye's early research and theoretical formulation which identified stomach ulcer as one of the non-specific responses to stress and a critical component of the general-adaptation-syndrome (Selye, 1949). The behavioral scientists have been intrigued by the possible etiological relevance of psychological stress, and have focused their attention on exploring and developing stress procedures which were effective in producing stomach lesions. However, a persistent outcome of these studies was that not all stressors resulted in stomach lesion, and not all animal subjects developed ulcers when exposed to an ulcerogenic psychological stressor. One way to reduce this subject variance was to increase the intensity of the stressor (ie increase grid shock intensity; increase the dura-

tion of stress exposure, etc), but it is difficult to conceive these operations as studies of psychological stress. Robert Ader (1971) accurately portrayed this problem when he stated, "Psychological factors do not, in themselves, cause ulceration, but in interaction with certain physical stimuli.., or biological predisposition (perhaps genetically determined) psychological factors can exert significant effects" (Ader, 1971). In spite of Ader's emphasis on the multi-factor etiology of stress ulcer, this laboratory focused most of its research efforts on the ulcerogenic characteristics of various environmental stressors (Par6, 1988). In one such study, we compared the ulcerogenic potency of supine-restraint stress and water-restraint stress. In supine restraint the rat is immobilized in a supine position on a plastic board with legs fastened to the board with nylon tape. The animal is then placed in a ventilated refrigerator with a temperature of l l"C for 2 h (Vincent et al, 1977). After the restraint session, the animal is released and returned to its home cage for a 2-h post stress period. In the water-restraint procedure the rat is loosely confined in a

230 PVC tube. The rat can move its limbs and move forward and backward, but cannot turn around. The tube, with the animal enclosed is placed in a water tank with the water level reaching the animal's neck. The water temperature is maintained at 18.5"C. After a 2-h water-restraint stress period, rats are released and returned to home cages for a 2-h rest period (Takagi et al, 1964; Murison and Overmeir, 1986). Following the post-stress rest period, the animals are killed and the stomach is inspected for ulcers. The number and length of ulcers are recorded. In these studies the cumulative length (mm) of all ulcers represents the measure of ulceration severity. We compared these two procedures using Long Evans rats and found that the water restraint procedure was significantly more ulcerogenic as compared to the supine restraint procedure (Par6, 1988).

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S t r a i n differences and stress u l c e r To ensure that the greater ulcerogenic effects of water-restraint stress were not specific only to Long-Evans rats, we subsequently exposed rats from six strains to either water-restraint stress or supine-restraint stress (Par6, 1989a). The rat strains observed included Wistar, Sprague-Dawley (SD), Fischer-344 (F-344), Long-Evans (L-E), spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) normotensive rats. In this study rats were food deprived for 48 h before restraint, and rats from each strain were exposed to either water restraint or supine-restraint, as described above. SHR, Wistar, and S-D rats were ulcer-resistant, whereas L-E, F-344, and WKY rats were ulcer-prone. In a more recent study we subjected rats from the Lewis strain, as well as the six strains previously studied, to the water-restraint procedures

(Par6, 1990). As figure 1 illustrates, Lewis rats were most resistant, and WKY rats least resistant to the restraint-induced stress ulcer. Since older rats are less susceptible to stress ulcer (Par6, 1986), one would expect that the ulcerogenic effect of water-restraint stress would diminish in older rats. To test this hypothesis we exposed 4-month, and 16-month old WKY, SHR, and F-344 rats to water-restraint and supine-restraint stress. This study revealed that WKY rats, as compared to SHR and F-344 rats, were more ulcer-prone and that age did not provide protection. Indeed, as table I demonstrates, the older WKY rats revealed the most severe ulcer scores (Par6, 1989a). The greater susceptibility to stress ulcer by WKY rats confirmed an earlier investigation from this laboratory which had reported that stress

Table I. Mean (_-+SE) cumulative length of ulcers (mm) for 4- and 16-month old SHR, WKY and Fischer-344 rats exposed to supine restraint and water restraint a 4 - M o n t h old rats Rats strains F-344

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a Reprinted with permission from Physiol Behav 45.

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ulcer was more prevalent in WKYs as compared to SHRs when these strains were exposed to either the restraint plus cold procedure or the activitystress ulcer paradigm (Par6 and Schimmel, 1986).

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Emotionality and stress ulcer Why were W K Y rats more susceptible to stress ulcer? Was it possible that these animals were more emotional and consequently more vulnerable to stress? This seemed to be a reasonable hypothesis since published data suggested a relationship between emotionality and ulcer incidence (Par6 and Vincent, 1981; Glavin, 1982). To test this hypothesis, we observed WKY, F-344, Wistar and SHR rats in the open field test of emotionality (Broadhurst, 1957) and subsequently exposed these animals to water-restraint stress (Par6, 1989b). Using the open-field criteria for emotionality (ie long response latency, and low ambulation, rearing and grooming scores), the strains were evaluated on this characteristic and the WKY rats were judged as significantly more emotional as compared to the other three stains (fig 2).

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232 A week later these animals along with control animals which had not been previously tested in the open-field, were subjected to the standard water-restraint ulcerogenic procedure. WKY rats, which had been judged as more emotional, subsequently produced the most severe ulcer scores when exposed to water-restraint stress (see fig 3).

Learned helplessness and stress ulcer If W K Y s were more emotional, was it reasonable to assume that these animals would also be more vulnerable to a learned helplessness procedure? There is evidence that emotional factors are related to the acquisition of the learned helplessness task (Drugan et al, 1985; Nijssen and Schelvis, 1987; Paul, 1988). In order to address this question, WKY, SHR, F-344 and Wistar rats were tested in a standardized learned helplessness paradigm (Drugan et al, 1984). This consisted of administering, on the first day, a series of 80 unavoidable tail shocks and on the next day testing these animals for escape performance in a two-way shuttle-box apparatus. The shuttle-box test required that the rat cross from one compart-

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233 ences between strains in either basal values, or after shock stress or following a reinstatement trial, in the threshold values for SHR and WKY rats. This would suggest that WKY rats were not hyperanalgesic, and the response deficit manifested in the shuttle-box situation was attributable to other factors.

the prevalence of depressive behavior in WKY rats. Was depression a characteristic of WKY rats? This notion was quickly investigated by inspecting data collected over 10 years ago in this laboratory, but published much later (Par6, 1989c). In that study we had tested SHR, WKY and Wistar rats in the Porsolt's forced-swimming, or 'behavioral despair' test (Porsolt et al, 1977) and subsequently exposed these animals to the activity-stress uicerogenic procedure (Par6, 1976). In the Porsolt test, the rat is placed in a large water tank and the behaviors of headshakes, bobbing, dives and the amount of time spent struggling and floating are recorded. The underlying assumption is that non-depressed animals are very active whereas depressed rats 'give up' and become relatively motionless in the water tank. Thus, depression is operationally defined in terms of low headshake, bobbing, diving and struggling

Depression and stress ulcer In reviewing the performance of the W K Y rat in the different test situations, we noted a group of behaviors which reflected a general retardation in behavior. These behaviors included long response latencies and slow ambulation in the open-field, slow movement and prevalence for freezing in the shuttle-box and very little struggling in the waterrestraint procedure. All these responses reflected

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234 scores, plus high floating scores (Borsini et al, 1984; O'Neil and Gertner 1986; Hilakivi and Hilakivi, 1987). This test is sensitive to antidepressants and has received considerable support from other investigators (Willner, 1984; Wallach and Hedley, 1979; Sunal, 1986; Arletti and Bertolini, 1987; Barros and Leite, 1987). The results of our study are outlined in figure 6. On the basis of these data, WKY rats were judged as more depressed. After exposure to the activity-stress ulcerogenic procedure, ulcer severity scores were significantly higher for WKY rats as compared to SHR and Wistar rats. These data are illustrated by figure 7. In addition, floating time scores predicted subsequent ulcer severity in WKY rats ( r = 0 . 5 8 , P < 0.05). The intriguing suggestion here is that the more 'depressed' WKY rats were also the most vulnerable to the ulcerogenic procedure. These findings were corroborated in a more recent study. Wistar, F-344, SHR and WKY rats were observed in Porsolt's forced-swimming test and a week later subjected to water-restraint as the ulcerogenic procedure. WKY rats were judged as more depressed, according to the Porsolt test, and these W K Y rats also developed significantly more ulcer when subsequently exposed to the water-restraint procedure (Par6, 1989b). In other test situations, the WKY rat demonstrates a characteristic immobility response when confronted with a stressor. In the defensive burying paradigm (Pellow and File, 1986) the rat will bury, with bedding material, a stationary prod that previously produced a shock stimulus. However, the W K Y rat, unlike other strains, will remain immobile after prod shock and not demonstrate the burying response (Par6, 1992). This stress-immobility relationship in WKY rats suggests that acquisition of a passive avoidance response would occur more rapidly with WKY rats. Indeed, W K Y rats acquire passive avoidance tasks faster than Wistar and F-344 rats (Par6, 1993). These data would suggest that the depressionlike behavior observed in our WKY rats is intimately involved in stress-ulcer susceptibility. This notion has not gone unnoticed within clinical circles. There are clinical reports (Piper et al, 1977; Feidman et al, 1986; Hernandez et al, 1988), which indicated that patients with depression symptoms are more prone to peptic ulcer disease. This also implies that manipulations which alleviate depression would also reduce stress ulcer. Partial support for this hypothesis was

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235 found in some unpublished data from this laboratory. In this study rats were exposed to the activity-stress ulcerogneic procedure and were injected twice daily with one dose level of three psychoactive drugs. As figure 8 reveals, the drug most effective in protecting against stress ulcer was the anti-depressant drug imipramine. We have recently reported that desipramine not only reduces immobility in the Porsolt test, but also reduces water-restraint stress ulcer in a dosedependent fashion (Par6, 1992a). Corroborative evidence for this finding has recently been presented by Hernandez and Xue (1989). While it is interesting to speculate that the anti-ulcer effects of imipramine may have resulted from the inhibition of depression mediating mechanisms, other factors would be considered. Imipramine, as a typical tricyclic antidepressant, may inhibit gastric acid secretion probably by blocking H2 histamine (Hernandez and Xue, 1989). Tricyclic antidepressants may also stimulate mucosal defense since trimipramine inhibits ethanol and hydrochloric acid induced ulcers (Richelson, 1982).

Anxiety and depression in WKY rats Some caution is warranted before we conclude that the behavior of our WKY rats can be described exclusively as depression. Gray (1985) and Redmond (1979) have argued that most unavoidable stress paradigms lead to an anxiety-depression state which most closely resembles clinical neurotic depression. Anisman and his colleagues (Anisman, 1975, 1984; Anisman and Zacharko, 1982) suggest that when animals are exposed to stress, they typically advance through two distinct stages. When stress is first applied, considerable excitation is observed (ie the activation phase). But if the stressor persists without successful coping by the animal (as is the case in unavoidable shock), a longer period of behavioral depression ensues during which the animal responds in a very passive fashion toward the stressor (ie the behavioral inhibition phase). This conceptualization has been succinctly reviewed by Glavin (1985). If we closely observe the behavior of our WKY rats in the stress-provoking situations described in this report, we note that the application of the stressor (eg grid shock, restraint) is followed by some behavior such as hopping, running, or struggling. Thus the possibility exists that the WKY rat does not enter the

stress situation in a depressed state but with a significant degree of anxiety and when the stressor is applied this animal progresses quickly through the activation phase to the second behavioral inhibition phase and freezes sooner than rats from other strains. This conceptualization is in agreement with Berger and Starzic (1988) who reported that both SHR and WKYs are emotionally reactive but that the stress coping style for the SHR is to move, whereas the WKY rat responds by freezing. Weiss (1985) summarizes the depression-anxiety debate by stating that "...uncontrollable shock as a method to create depression may best reproduce anxious depression or at least depressive conditions that contain anxiety as an adjunctive feature" (Weiss, 1985). The relationship between anxiety and depression is also noted in the clinical literature (Dealy et al, 1981; Dunnet, 1986). It would seem that anxiety is one of the behavioral components of the WKY animal model and that depression is a symptom of the stressresponse set of this model. The neurotransmitter systems which possibly mediate this state have been reviewed extensively elsewhere (Anisman, 1984; Glavin, 1985; Weiss, 1985; Gold et al, 1988) and it is reasonable to assume that these systems are involved in this disease process. We suggest that the WKY rat is emotionally very reactive to stress and this high degree of reactivity is manifested by behavioral signs of depression. Furthermore, the depressive behavior predisposes the WKY rat to stress ulcer. This depression ulcer syndrome may be mediated by a heightened reactivity of the hypothalamic pituitary adrenal (HPA) axis to stress. This hyper-reactivity of the HPA axis may result either from a hypersecretion of corticotropin-releasing-factor (CRF) and arginine vasopressin (AVP) or a hyper-responsiveness of the pituitary in the WKY rat to CRF and AVE We made a preliminary test of this hypothesis by monitoring plasma ACTH and corticosterone levels in WKY and Wistar rats exposed to restraint plus cold stress. Jugular catheters, connected to vascular access ports, were surgically implanted. The device permitted multiple serial samples to be collected. After daily home cage basal samples were collected, all rats were restrained in a prone position and exposed to a cold environment of 11°C for 2 h. Blood samples were collected at 0, 5, 10, 20, 40, 60, and 120 min for ACTH and corticosterone determinations. Rats were subsequently killed and stomachs inspected

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for ulcers. The ACTH and corticosterone data are presented in figure 9. There were no strain differences in basal ACTH concentration, but the ACTH stress response was significantly greater for WKY rats throughout the stress period F(1,8) = 13.23, P < 0.01. Surprisingly, there were no differences in plasma corticosterone concentrations between WKY and Wistar rats, F(I,8) = 0.25. The fact that both basal and stress-stimulated levels of corticosterone were identical in both strains suggests the presence of an appropriate negative glucocorticoid feedback signal. Therefore, the continually exaggerated ACTH response to stress cannot be attributed to a faulty feedback at the pituitary level, but to an elevated secretion of CRF and/or AVP, or to a greater sensitivity of the pituitary to those secretagogues. In addition, none of the Wistar rats had ulcers in this study, whereas all the WKY rats had ulcers.

Discussion In these studies we have observed that water restraint is more ulcerogenic than supine restraint and that WKY rats, as compared to other rat strains, are significantly more susceptible to water restraint-induced stress ulcer. When tested in procedures which are considered sensitive measures of behavioral depression (eg learned helplessness, forced-swimming test), the WKY strain is judged as the most depressed strain and a high positive

correlation is obtained for WKYs between measures of depression and ulcer severity scores. The hyper-responsiveness of WKY rats to stressor stimulation is also emphasized by the significantly higher levels of plasma ACTH in response to restraint stress. The presence of appropriate corticosterone negative feedback signal suggests either a hyperactivity of the pituitary to stress in WKY rats or an increase in secretagogues which drive the pituitary. Thus, we have observed the following in WKY rat: 1) a high level of activity of the HPA axis in response to stress; 2) depressive behavior; and 3) high susceptibility to stress ulcer. These observations suggest that the WKY rat is an ideal strain to study the etiology of stress ulcer disease in a genetically predisposed animal. There are, of course, other studies which have demonstrated strain differences in ulcer susceptibility (Sawrey and Long, 1962; Par6, 1972; Urushidami et al, 1975; Driscoll et al, 1983). For instance, Sines (Sines and Eagleton, 1961; Sines et al, 1963; Sines, 1971) selectively bred Sprague-Dawley rats for ulcer susceptibility, and Ackerman demonstrated a stress-ulcer susceptibility in genetically obese mice (Greenburg and Ackerman, 1984). But in those studies, susceptibility to stress ulcer was the major, if not the only, differentiating factor. On the other hand, our studies revealed that WKYs are not only stress-ulcer prone, but manifest a behavioral component - depressive behavior - and this syndrome has greater clinical relevance.

237 We are reminded of our original counsel by Ader (1971) that psychological stress by itself is usually not sufficient to cause disease, but in combination with other physical and genetic factors, can produce disease. Thus, given an ulcerogenic stressor, disease will occur in only a percentage of animals exposed, and much of the variance in the outcome measure is attributable to genetic and environmental predisposing factors. Jeffrey Gray (1980) wonders why a seemingly innocuous stressor can cause profound disturbances in some subjects and not in others. Gray, however, resolves this dilemma by acknowledging that the proper study of psychopathology involves an examination of psychological stress within the predisposing personality. It is for these reasons that we feel that the WKY animal model represents an ideal opportunity for the study or stress-ulcer. It may well represent the only known readily available rat model which manifests a predisposition of depressive behavior. Its vulnerability to stress-ulcer disease and its stress-coping characteristics allow investigators to study depressive behavior and stress-ulcer as well as responsible neuroendocrine mediating mechanisms.

Acknowledgement This research was supported by the Department of Veterans Affairs and by the Research Foundation of the University of Pennsylvania.

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