Restraint stress in biomedical research: A review

Neuroscience &BiobehavioralReviews, Vol. 10, pp. 339-370, 1986. ©AnkhoInternationalInc. Printedin the U.S.A.

0149-7634/86$3.00 + .00

Restraint Stress in Biomedical Research: A R e v i e w I W I L L I A M P. PARI~

Veterans Administration Medical Center, Perry Point, MD 21902 AND G A R Y B. G L A V I N

Department of Pharmacology and Therapeutics, Faculty of Medicine University of Manitoba, Winnipeg, Canada R3E OW3 R e c e i v e d I0 F e b r u a r y 1986 PARI~, W. P. AND G. B. GLAVIN. Restraint stress in biomedical research: A review. NEUROSCI BIOBEHAV REV 10(3) 339-370, 1986.--The use of restraint or immobilization for investigations of animal physiology, pathology and pharmacology has an extensive history. The major use of this technique has been as a "stressor" for the induction of stress response syndromes in animals. Many such syndromes have been characterized from the behavioral level to the neurochemical concomitants of stress. As a consequence of this particular use of the restraint procedure, much information concerning drug effects on stress response syndromes has been obtained. Indeed, many researchers in the area of gastrointestinal drugs routinely screen their new compounds in a restraint model of gastric stress ulcer. The purpose of this review is to present for researchers, a summary of the methods for, the parameters of, and known drug effects on, restraintinduced pathology. In our experience, this technique has proven to be a very useful one for the examination of both central and peripheral mechanisms of stress-related disorders, as well as for studying drug effects upon these disorders. Restraint

Stress

Drug screening

Ulcer

"primed" by emptying via food deprivation prior to the induction of restraint stress. However, early workers used periods of 48 to 72 hours of pre-stress starvation and often produced only ulcers located in the rat forestomach (rumen), which are indicative of starvation [265] and are not relevant to human gastric disease. A second problem with the early restraint-induced ulcer work concerned the nature of the gastric glandular damage produced by these techniques. Very few actual ulcers (i.e., damage peyietrating the muscularis mucosa) were produced--most of the pathological changes were more properly classified as surface erosions and petechiae. Such findings did not negate the use of the restraint methodology, however, the relevance of the data to human gastrointestinal disease was questioned. In 1971, Lee and Bianchi [191] proposed several criteria which could be used to assess the validity and efficacy of experimental ulcer models. Subsequently, several restraint procedures were developed which satisfied these criteria, including those which: (a) minimized pre-stress starvation, (b) produced true ulcer (and other manifestations of stress pathology) in a variety of animal species, (c) produced gastric damage which responded to current drug therapies, and (d) minimized the duration of actual stress applied to the animal [361]. Most effective restraint procedures now in-

IN 1936, Selye [308] reported that certain physiological changes occurred in experimental animals exposed to a wide variety of stressors. These changes represented some of the classic signs of the stress syndrome--adrenal hypertrophy and thymicolymphatic involution. In a separate publication in the same year, he noted that acute ulcers of the digestive tract were observed in rats exposed to non-specific stressors [309]. Selye observed that immobilizing or restraining the rat led to the manifestation of his stress syndrome [308]. Since that time, many different restraint procedures have been used. In the 1950's, Bonfils and his colleagues [36] popularized the restraint procedure which was associated with the development of gastric lesions. The restraint technique was intensively studied in North America by Brodie and his co-workers [43-48] and the area was reviewed by Brodie in 1971 [43]. Since that review, many new and highly effective procedures have been developed for immobilizing animals and the data generated have expanded to include central neurochemical consequences of stress, as well as drug effects upon these responses. One concern in early restraint work was the rather lengthy starvation period often used prior to the actual restraint. Most workers recognized then, as now, that experimental ulcers are more reliably produced if the gut is

tSupported by NSERC, Manitoba Health Research Council, Health Sciences Center Research Foundation, University of Manitoba Faculty Fund and the Veterans Administration.

339

340

PARIS; AND GLAVIN TABLE 1 A B B R E V I A T I O N S A N D SYMBOLS

AD ASA CCK CRF DA DBH 5-HIAA 5-HT GSH icv ig im ip iv LHRH MHPG-SO4 MNR MR NA NS NT PCPA PNMT po sc SD SHR TRH VIP WKY ~" ~,

adrenaline acetylsalicylicacid cholecystokinin corticotropin releasing factor dopamine dopamine beta hydroxylase 5-hydroxyindoleaceticacid 5-hydroxytryptamine; serotonin reduced glutathione intracerebroventricular intragastric intramuscular intraperitoneal intravenous luteinizing hormone releasing hormone 3-mthoxy-4-hydroxyphenylethyleneglycolsulfate Maudsley non-reactive Maudsley reactive noradrenaline non-significant neurotensin para-chlorophenylalanine phenylethanolamine N-methyltransferase by mouth subcutaneous Sprague-Dawley spontaneously hypertensive rat thyroliberin (TSH-releasing hormone) vascoactive intestinal peptide Wistar Kyoto normotensive control for SHR increase decrease

volve 12 hours or less of pre-stress starvation, immobilize the animal for 1 to 5 hours, and are associated with a variety of both central and peripheral changes indicative of stress, including: atrophy of the thymus and spleen [308], adrenal hypertrophy [308], elevated plasma corticosterone, fatty acids, and glucose levels [103, 116, 252], gastric ulcers [361], reduced gastrointestinal transit [17], hypothermia [226], and accelerated noradrenaline and dopamine turnover in many brain regions [116]. These simple, effective, reliable, and reproducible models for the rapid induction of stress response syndromes have seen widespread use in the literature. We review herein the literature examining the most salient parameters affecting restraint stress (Tables 2 through 10) and the major use to which restraint has been p u t - - t h a t is, the examination of drug effects (Table 11). The restraint procedure historically was used as an experimental procedure for producing gastric lesions in the rat. It was later used as a standard stress procedure for the purpose of observing the various physiological and biochemical responses to stress. Accordingly, this review focused primarily on the effects of restraint stress on gastrointestinal pathology, and as a secondary objective attempted to summarize the more recent work on the effects of restraint on biological markers of stress. In most instances, we have provided a brief summary of the major effects for the parameters reviewed. The

purpose of this review was to organize the published literature according to standard subject parameters (e.g., strain, species, age and sex) and common experimental manipulations (e.g., restraint duration, diets, diurnal variations, drugs). It was not the main intent of this review to provide a critical evaluation of all the studies cited. Therefore, we have attempted to provide information useful to the researcher, not only in the text of this article, but primarily in Tables 2 through 11, which summarize these studies with the use of abbreviations and notations. For the sake of brevity, a number of abbreviations have been adopted for this review. These are listed in Table 1. RESTRAINT TECHNIQUES

Selye's initial restraint procedure involved tying the rat's legs together and wrapping the rat tightly in a towel [308]. However restraint, as an ulcer-producing technique was not studied intensively until nearly two decades later. During the 1950's a flurry of studies was conducted, mostly in France, which studied basic restraint parameters. There was an early concern to refine the restraint procedure so that ulcerogenic effects would be observed in a greater percentage of restrained rats. A robust restraint technique would reduce subject variability, encourage replicating studies, and at the same time provide an economical and cost-effective technique for studying stress effects in the rat. Modifications of the restraint technique are summarized in Table 2. At least three conclusions can be drawn from these studies. First, as restraint became more intense and immobilization more complete, the incidence of rats with lesions increased. Second, if additional stressors (e.g., cold, water immersion) were added to the restraint procedure, ulcer incidence increased. It is interesting to note that in 1943 Selye [310] commented that the addition of stressors such as starvation and cold facilitated the development of ulcers in the rat. Finally, as the restraint stressor became more intense, or if multiple stressors were used, the stress-exposure time necessary to yield high ulcer incidence decreased. D U R A T I O N OF R E S T R A I N T

Table 3 summarizes studies using restraint where varying the duration of stress was the main focus. There is some variability in these studies depending upon the method of restraint, but the majority of studies suggest that increasing the duration of restraint increases the degree of stress pathology observed. This relationship may change if other conditions of the restraint procedure are modified. F o r example, the length of the restraint period necessary to produce ulcers may diminish if the severity of the restraint stressor increases [194,337], or if the length of the prerestraint food-deprivation period increases [55]. N U M B E R OF R E S T R A I N T EPISODES

An exception to the restraint-duration ulcer relationship appears to those studies wherein repeated episodes of restraint, separated by stress-free periods, are used to assess adaptation/sensitization of stress response syndromes. As Table 4 indicates, there are very few studies concerned with this issue, and the difference in procedures precludes a simple analysis of these data. However, it would appear that animals can adapt to repeated restraint episodes and that this adaptation depends in part on the ratio of free-time to re-

RESTRAINT STRESS

341

TABLE 2 RESTRAINING TECHNIQUES

Investigator(s), Year

Experimental Procedure

Rossi, Bonfils, Liefooghe and Lambling, 1956

Wrapped in hardware cloth screening; legs protuding through holes and tied together. Screen cylinder suspended horizontally from buret clamp. restrained 20 hr. Reducing cage volume (ccm); 24 hr 7,354 cm 3 1,260 cm 3 756 cm a 562 cm 3 361 cm 3 180 cm a Prone restraint on a board; fimbs outstretched and tied with tape; 24 hr. Window screen envelope, stapled close around rat; 24 hr. Wrapped in plaster of Paris bandage forming cocoon; 24 hr. Window screen restrainer plus exposure to 5°--6°C cold; 1 hr Supine restraint on board plus immersion to xiphoid in 25°C water; 20 hr. Cylindrical plaster of Paris corset fitted around torso; 24 hr. Bonfds-type screen restrainer plus exposure to different temperatures, 2.5 hr. 140C 19°C 22°C 24oc 28oC 32oc Quonset hut plastic restrainer cage, plus 4°-7°C cold; 2 hr. Cylindrical metal tube restrainer plus exposure to different temperatures; 24 hr. 19°C 22°C 25°C 28°C Immobilized in standing position with feet secured in chocks, plus lmA footshock; 20 hr. Prone restraint on board, plus exposure to 4°-7°C cold; 3 hr.

Bonfils, Liefooghe, Rossi and Lambling, 1959

Renaud, 1959

Brodie and Hanson, 1960 Sines, 1960 Brodie and Valitski, 1963 Takagi, Kasuya and Watanabe, 1964 Mikhail and Holland, 1966 Buchel and Gallaire; 1967

Senay and Lcvine, 1967 Martin, Martin, and Lambert, 1970

Buchanan and Canl, 1974

Vincent, Glavin Rutkowski and Pare, 1977

Percent Rats With Ulcers

Ref.

95%

293

37 12% 14% 19% 31% 47% 86% no data

279

86%

44

100%

317

90%

48

100~

337

75%

221 55

95% 86% 70% 33% 26% 21% 66%

312 207

100% 67% 17% 25% 100%

54

100%

361

342

PARE AND GLAVIN TABLE 3 DURATION OF RESTRAINT Duration 2.5, 5, 10, 20, 40, 80 min; 4, 15 min; 1,7, 17, 24 hr 5-240 rain 5, 10, 10, 30, min; 2.5 hr 10, 20, 30, rain; 1, 1.5, 2 hr 15, 30, 60, 120,240 min

30 mill, 4 hr 30 min, 2, 4, 6, 18, 24 hr 30, 60, 120, 140 rain 30 min; 1, 2, 4, 6, 8, 12, 24 hr 30 rain 2, 7 hr 30,60, 120,240min 30-120 min 30-300 min 1-6 hr 0, 1, 2, 3, 6, 12, 18 hr 0, 6, 12, 18, 24 hr 1-48 hr 1, 2, 3, 6, 7, 25 hr 1,2, 3, 5 hr

1,4, 24 hr 2, 8, 14, 18 hr 2, 6, 12, 24 hr

2, 3, 4, 6 hr 3, 24 hr 4, 8, 12, 16, 20 hr 4, 8, 12, 16, 20 hr 4, 8, 24, 40 hr 4, 6, 8, 12, 24, 36, 48, 60 hr 4, 8, 12, 16, 21 hr 4, 20 hr 6, 12, 20 hr 6, 18, 24, 36, 54, 72, 90 hr 6 18 hr

Effects 1' corticosterone until 80 min; ~ at 24 hr ~ cardiac phospholipid and fatty acid content with duration $ intestinal transit time 1' adrenal cAMP with duration ~ brain histamine with duration ~ corticosterone; adrenalNA; hypothalamic NA, struggling behavior with duration; no change in brainstem NA; hypothalamic DA remained elevated throughout ~ mast cell number; I' gastric blood flow; pH 1' 1' ulcer, 1' vascular engorgement with duration 1" corticosterone with duration; plasma renin 1' until 60 min; J, thereafter 1" ulcers to 6 hr, then no change; intragastric pH ~ up to 2 hr, then normal; serum gastrin I" up to 6 hr ~ PGE2; 1' ulcer with duration 1' PGE2;andPGE2;c~upto 120min 1' brain 5-HIAA with duration; 1' corticosterone with duration 1' brain 5-HIAA with duration; 1' corticosterone with duration ulcer severity 1' with duration ulcer severity 1" with duration ulcer severity 1" with duration 1' gastric hemorrhage at 24 hr, then until 48 hr gastric acid 1" up to 6 hr; then $ ; 1' with duration 1' brain 5-HT up to 3 hr; DA ~ up to 1 hr; no change in NA; corticosterone 1" with duration no effect on brain acetylcholine $ ulcer with duration 1" incorporation of 3~S sulfate into gastric sulfated glycoproteins up to 12 hr $ brain NA with duration biphasic gastric acid response: then no change ~ ulcer incidence and severity with duration 1" ulcer incidence with duration 1' ulcer severity with duration; mast cells with duration I" ulcer with duration; maximum hydrothorax at 24 hr 1" ulcer and $ gastric acid output with duration 1' ulcer with duration no differences in ulcer; plasma pepsinogen level ulcer incidence I' with duration ulcer and corticosterone in rats from larger litters with duration

Reference 296 275 51 268 347 170

135 133 314 370

18 32 343 222 40 389 140 238 177 281

53 189 228

285 49 113 125 201 287 292 341 6 44 130

RESTRAINT STRESS

343 TABLE 3 CONTINUED

Duration

Effects

6, 12, 18, 24 hr

6, 48 hr 6, 8, 18, 24 hr 6, 8 hr 7, 24 hr 12, 16 hr 20 hr 12, 24, 48 hr 18, 24 hr 24, 48, 72, 96 hr 24, 48 hr

Reference

1' ulcer with duration; ~, incorporation of radio labelled sulfated glycoproteins incorporated into gastric mucosa with duration ( ~ mucosal resistance) No difference in ulcer incidence or severity t ulcer with duration no difference in ulcer incidence ulcer t with duration no difference in urinary catecholamines early Borffils study; 95% rats with ulcers no differences in ulcer incidence ~, core temperature with duration ~ glandular ulcer with duration 1` incidence of fetal resorption and neonatal cleft palate with duration

186

320 33 213 36 127 293 374 345 114 291

TABLE 4 NUMBER OF RESTRAINTEPISODES Experimental Treatment

Outcome

24-hr restraint, 48-hr rest; 1--4episodes 18-hr restraint, 6-hr rest; 1-5 episodes 3-hr restraint, 21-hr rest; 1, 2, 4, and 8 episodes 3-hr/day for 1-8 weeks 2.5-hr restraint, 21.5-hr rest; 1, 4, 7, 9, 14 episodes 2-hr restraint, 23-hr rest; 7 episodes 1-hr/day, 3-6 daily episodes 30 rain/day, 5 days

Ulcer incidence peaks after I episode; diminishes thereafter Ulcer incidence peaks after 4 and 5 episodes Ulcer incidence peaks after 4 episodes

362

Improved cold tolerance; no ulcer data Ulcer incidence peaks after 1st episode

182 331

Ulceration not observed; t brain 5 HT

173

15 rain/day, 1 and 10 days

Reference

Ulceration not recorded; 1' adrenal PNMT and DBH Restraint-induced t in plasma corticosterone ~ after Day 2; brain NA t on Day 1, ~ thereafter 1' pituitary cyclic AMP, plasma corticosterone and prolactin, ~ growth hormone. Response attenuated after ! 0 days

straint time. In other words, as the length of the intervening rest period increases in relation to the duration of the restraint period, animals adapt more readily to the restraint procedure. F o r instance, in the Brodie and H a n s o n study [44], rats were allowed only a 6-hr rest period between 18-hr restraint sessions; no adaptation was observed in this study. But in the earlier Bonfils, Liefooghe, Rossi and Lambling study [37], 48-hr of rest i n t e r v e n e d b e t w e e n the 24-hr re-

37 44

65 170

167

straint episodes and ulcer incidence diminished after the first restraint session. If the rest period exceeds the stress periods, rats generally adapt to repeated stress episodes. F o r example, Stone and Platt [331] found that rats subjected to repeated, discrete episodes of restraint stress, gradually adapted to this form of stress and, over time, exhibited less anorexia and fewer gastric lesions. In addition, and correlating very strongly with these peripheral adaptive responses,

344

PARE AND GLAVtN TABLE 5 STRAIN AND SPECIES D I F F E R E N C E S

Species or Strain

Effects

Rats, mice, guinea pigs, hamsters, rabbits, monkeys

mice > rats > guinea pigs > hamsters in no. of ulcers; no ulcers in rabbits or monkeys; 1' length of restraint 1' ulcer incidence; bilateral adrenalectomy 1' incidence and severity of ulcers monkeys; ulcers appear after 2 hrs spread through stomach 6 hrs poststress; dogs, pigs; ulcers after 12 hrs of stress Ulcer incidence: (prone restraint) rat =guinea pig= hamster=gerbil > mouse; (supine restraint) rat =guinea pig= mouse > hamster > gerbil 1' ulcer in Wistar > SD > Long Evans No. of ulcers: SD > SHR > Wistar SD > ulcer than Wistar=Long Evans hypertensive had > 1' in corticosterone output; ~, with repeated stress no difference 1' SHR > WKY for plasma levels of DBH, adrenaline, NA; blood pressure > in WKY, 4 hrs post stress SHR levels > WKY for DBH, adrenaline, NA MR > incidence and severity of ulcer than MNR MR > MNR F4 > other strains; SD < all others for males F4 > all other except Fischer 344 for females 30 days individual housing ~ ulceration

Rats, dogs, pigs, monkeys

Rat, guinea pig, mouse hamster, gerbil

SD, Wistar, Long Evans SD, Wistar, SHR SD, Wistar, Long-Evans SD, Wistar, Long-Evans, Fischer MR, MNR SHR, WKY

MR, MNR MR, MNR F4, Irish (Axe), Fischer 344, August 33322, SD. [male, female] SD; 13th generation of stress ulcer susceptible

Reference 44

241

117

11 122 114 170 220 212

219 217 319

320

rats

Hooded Wistar, Wistar, SD SD; Holtzman, Charles River SHR, WKY

SD, F344, Lew Long-Evans, Brattleboro rat s

Wistar > Hooded Wistar > SD SD (Holtzman) > SD (CR) WKY > SHR ulceration; ~ arterial blood pressure in both; heart rate ~ in SHR; plasma adrenaline, NA 1' in both; SHR > hypothermia Fischer 344 1` PNMT Length of ulcers: Brattleboro > Long-Evans

was a decrease in the n u m b e r and sensitivity of brain betaadrenergic receptors. Stone d e v e l o p e d an elegant hypothesis suggesting that the p r e d o m i n a n t feature of adaptation to stress and one which may determine coping ability, involves a reduction in, or c o n s e r v a t i o n of, the magnitude o f the central noradrenergic responses to stress, especially in limbic brain structures such as the hypothalamus. Challenging this view, h o w e v e r , is a recent study by Kant et al. [168]. Using a " c r o s s - s t r e s s o r " design, animals w e r e first e x p o s e d to episodes o f either restraint, foot-shock or forced running o v e r a period o f 10 days. T h e s e stressors

379 192 21

52 377

were chosen on the basis of both their behavioral dissimilarity, and their ability to induce highly similar biochemical responses (elevated plasma c o r t i c o s t e r o n e and prolactin, and e l e v a t e d pituitary cAMP). Following the 10-day exposure period, the animals w e r e challenged with either the same or a different stressor. Adaptation, as defined by corticosterone, prolactin and pituitary c A M P , was o b s e r v e d only w h e n the animals w e r e challenged with the s a m e stressor to which they had b e e n e x p o s e d in the prior 10 day period. Adaptation was not o b s e r v e d w h e n the animals w e r e exposed to a n o v e l stressor. K a n t et al. [168] suggested that

RESTRAINT STRESS

345 TABLE 6 AGE DIFFERENCES

23, 30, 35, 50, 70, 200 days

23 days, 9.5-11.5 weeks

1, 2, 13months

40, 570days 6,8,10,12weeks 6, 8, 10, 12 weeks 2,7, 12too. 2, 6, 11, 18, 26 months 2, 10, 15 months

2, 12 months

3 months, 2 yr

3, 8 months

98--131,238-278 days 4--6 months, 22-28 months 3, 10, 28 months, brief 30-min restraint Mice 3-4 and 5-6 weeks 100, 140, 180, 220grats 50, 92, 185,265 g rats

premature weaning at 16 days 100 > ulcer than 30 days; 100 males < females when normally weaned 23 days--5 day fasted during restraint > ulcer than older rats and nonrestrained same age 1, 13 months body temp adapted to repeated restraint 13 months > 1, 2 months for number of ulcers; oldest rats > adaptation no age difference severity in 6, 8 week >; 12 week no sig. ulceration ulceration with 1' age 7 months > 2 months > 12 months for No. of ulcers cimetidine ~ except in 18, 26 months; least effect on 26 month old restraint 1' NA turnover in all regions for all ages; T in MHPG-SO4 > in hypoth of 2 months than 15 months restraint 1' MPHG-SO4 in all regions for both ages; 2 months levels after 6 hr--12 month after 6, 24 hr 1' in hypothalamus, amygdala, pons and medulla, midbrain; in amygdala NA 1' after 6 hr for 12 months; 1' corticosterone at 6, 24 hr for 12 months old male > young awake male > young asleep male for baseline CA levels; repeated stress caused habituation in young males young maintain NA in telencephalon, older 30% and continue to ~ ; in cold room young maintain body temp. for 6 hr after 3 hr telenceph NA ~, 20%. ulcer susceptibility: younger rats > older rats greater ~ in adrenocorticai responsiveness no age differences 3-4 week > for ulcer severity ,L ulcer incidence with 1' in body weight $ ulcer incidence with 1' in body weight

adaptation to stress is largely due to behavioral e x p e r i e n c e (desensitization) with a particular stressor and not due to a general biochemical adaptive response. PRE-RESTRAINT FOOD-DEPRIVATION PERIOD Table 3 suggests that m a n y investigators have b e e n concerned with studying the effect o f restraint duration on ulcer incidence. In contrast, few investigators have been concerned with studying how the pre-restraint deprivation variable influences ulcer incidence. In an early study Buchel and Gallaire [55] c o m p a r e d a 0-hr (i.e., no deprivation) to a 26.5 hr deprivation period in rats e x p o s e d to episodes o f restraint ranging from 1 to 7 hr of restraint. N o n - d e p r i v e d rats did reveal ulcers, h o w e v e r the severity of ulcers was greater in rats f o o d - d e p r i v e d for 26.5 hr prior to restraint. In a m o r e recent study, Vincent, Glavin, R u t k o w s k i and Pare [361]

88

270

362

126 378 376 267 266 162

163

77

285

220 282 261 98 382 44

c o m p a r e d rats which had been f o o d - d e p r i v e d for either 0, 3, 6, 12, 18, or 24 hr prior to 3 hr of supine restraint plus 6°C cold. All f o o d - d e p r i v e d rats r e v e a l e d s t o m a c h ulcers, but ulcer severity was greatest in rats d e p r i v e d for 12 hr as compared to all the other deprivation treatments. STRAIN/SPECIES DIFFERENCES Differences in stress responses o b s e r v e d among different species and among different strains (mostly different rat strains) are largely d e p e n d e n t upon the nature of the stressor e m p l o y e d . M a n y failures to replicate findings can be traced to strain, and in s o m e cases, species differences. Although not dealing directly with restraint, our earlier work e v e n highlighted differences o b s e r v e d in stress responses within a strain and species, from rats which w e r e obtained from different vendors [263]. Selection of strain, species and vendor,

346

PARE AND GLAVIN TABLE 7 SEX DIFFERENCES Experimental Outcome

Reference

Wistar fern. more ulcers than SD females Females more active than males Males more ulcers than females when crowded 100 day males less ulcers than females when normally weaned; males more ulcers than females when prematurely weaned More ulcer in females than males when food deprived 24 hr 19 hr restraint diestrous females had more ulcers Prenatally stressed male offspring sig. fewer ulcers than male offspring of non-stressed females; females showed no differences No sig. differences between male and female rats restrained 2.5 hr

11 12 56

88 347 158

107 55

TABLE 8 DIETARYEFFECTS Diet

Effect

Reference

Milk and cream, milk and corn oil, sustagen, two special diets (milk and vegetable based) 3x daily Casein, sucrose salts USP XIV, corn oil, dehydrated liver, vitamin mix, choline Banana pulp (air dried) 48 hr Presweetened banana pulp (air dried) Pyridoxine deficient diet for 3 months Pyridoxine deficient diet 15% by weight corn/corn oil diet; one group 0.25 g l-tryptophan/lO0 g diet added Magnesium-deficient diet for 21 days prior to 18-hr restraint

all diets promoted healing

22

all diets 1' dental caries

327

~ ulceration J, ulceration caused by restraint no ], when caused by prednisolone ~ :ulceration; ~ gastric acid secretion no effect tryptophan deficient showed > ulceration

298 299

1" ulcer incidence and severity in rats

205

as well as the choice of stressor, are obviously important pre-experimental considerations if researchers are to avoid the inadvertent selection of unusually susceptible or unusually resistant subjects. Other workers, notably Sines and his colleagues [316--323], have exploited ulcer resistance/susceptibility in attempting to selectively breed for this trait. Sines developed the stress-ulcer-susceptible (SUS) strain of rat which was particularly sensitive to restraint-stress ulcerogenesis, SUS rats exhibited characteristics such as lighter body weight, greater "emotionality" (defined by their open-field behavior), and,

349 99 243

in the case of the females, less success at breeding. Similar observations were noted with the Mandsley reactive (MR) and non-reactive (MNR) strains developed in England [217,220]. Studies on strain effects overlap with studies investigating the relationship between restraint-ulcer susceptibility and characteristics of the animals, such as open-field "emotionality." Some early studies failed to observe any relationship between ulceration and emotionality [220] but positive results were forthcoming [217, 316, 318]. More recently, Glavin and Ykema [118] reported that rats judged as "high-emotional" in the open-field test were more suscepti-

R E S T R A I N T STRESS

347 TABLE 9 DIURNALAND SEASONALVARIATIONS

Time/Season of Restraint

Effect

Peak or trough of activity cycle

1' ulceration at peak of activity cycle, no food deprivation no ulcer in trough of cycle 1` ulceration at peak of activity cycle maximum ulceration in December; minimum in June most ulcers appeared during first 6 hr regardless of onset time of stress 1' day phenethylamine excretion; no effect on pH, creatinine, volume nocturnal 1' MHPG-SO4 at 30 rain in hypothalamus, at 60 rain in hypothalamus, amygdala; ~ NA at 60 rain in thalamus, midbraln, pons + medulla greater depletion of gastric and hepatic GSH level for 1400 hr-1600 hr; less for 2000 hr-2400 hr greater 1' in corticosterone in morning; no diurnal variation in NA; no effect on DA

Peak or trough of activity cycle January through December 0, 3, 6, 9, 12, 15, 18, 21mhour at which restraint began Days, night

13:00 hr, 01:00 hr

2000 hr-2400 hr; 0900 hr-1300 hr 1400 hr-1800 hr 1000 hr; 1700 hr

ble to restraint-ulcer. Ossenkopp and Mazmanian [257] reported that the best predictor of ulcer incidence was autonomic reactivity, an emotionality measure based mainly on defecation in an open-field test situation. Other species and strain differences are listed in Table 5. AGE EFFECTS Although the definition of an " a g e d " animal varies considerably in the literature, it generally appears that " o l d e r " animals do not necessarily exhibit more severe stress responses than " y o u n g e r " animals. However, as Table 6 would indicate, age does appear to be associated with slower recovery from a stressful challenge. F o r example, Ida et al. [163] found that " o l d e r " rats subjected to restraint stress exhibited prolonged elevation in plasma corticosterone levels. In addition, " o l d e r " rats were much slower than " y o u n g e r " animals in recovering normal brain noradrenergic function (slower N A turnover), especially in the hypothalamus, amygdala, pons plus medulla and midbrain. Thus, while differences between " y o u n g " and " o l d " animals in terms of the m a g n i t u d e of the stress response may not be consistently observed, at least some work suggests that aging is associated with a longer d u r a t i o n of responses to restraint stress. SEX DIFFERENCES As Table 7 would suggest, few consistent results have been obtained regarding sex differences in restraint-stress ulcerogenesis. This may largely be due to the regular five day estrous cycle of the female rat, and its accompanying activity cycle. Since the seminal work of Ader [7], it is clear that the relationship between the applied stressor and the animal's

Reference

10 7 380 86 348 354

41 351

activity level must be considered in evaluating the observed stress responses. Ader noted that restraining rats at the peak of their activity cycle was associated with gastric ulcer development, while restraint stress applied during their inactive phase produced no evidence of ulceration. Thus, observed sex differences, or lack thereof, may simply reflect that point in the female's activity cycle (peak or trough) at which restraint is applied. The majority of the work employing restraint stress has routinely used male animals to obviate this problem. Finally, Natelson et al. [242] recently suggested that gender p e r se may not be an essential causative factor in stress ulcerogenesis, but rather it exerts a permissive role which is enabled only upon challenge by some stressors. Analysis of some sensitizing agents in restraint ulcer production confirmed their hypothesis and may also account for some of the variability observed in male and female animals' responses to stress. DIETARY EFFECTS With the development and wide use of histamine H2 receptor-blocking drugs for the therapy of gastric and duodenal ulcer, dietary manipulations have received less attention in the experimental literature. One consistent finding has been the anti-ulcerogenic effect of banana, and banana extracts, which reduce restraint-induced [298], as well as phenylbutazone-induced, and histamine-induced [300] gastric ulcers. These studies are listed in Table 8. The banana effect may be related to its high 5-HT content [325], although restraint stress has been shown to elevate brain 5-HT levels, and depletion of brain 5-HT with PCPA does not correlate with augmented stress responses [303]. However, Gupta and Bhargava [132] indicated that centrally administered 5-HT enhances restraint ulcer formation. Recently, Goel, Gupta,

348

PARE AND GLAVIN T A B L E 10 POST-RESTRAINT/HEALING EFFECTS Recovery Time and/or Treatment 3 hr saline, histamine, scopolamine, atropine, carbachol 24 to 72 hr post 24 hr restraint 16--48 hr 20, 60, 120 min, 1, 4, 24 hr

48, 72 hr conditioned anxiety 15, 39, 63, 87 hr

1, 4, 24 hr

7, 24, 48, 72, 96 hr

2, 5, 10, 15, 20 min 2, 5, 10, 15, 30, 45 min 90 min and/or AI2(OH)3

30 min and one of phenylbutazone, ASA, sulfonate, 5-pyrazoione, reserpine, methylprednisolone 48, 96, 144 hr 2 hr 6, 24 hr

24 hr

1, 3, 6, 24 hr

0-3 hr, and 0--48 after 3 hr supine-restraint 0, 12, 24, 48, 72 hr after 24 hr restraint 0 and 2 hr after 6 hr restraint + shock 1-9 days after 24 hr restraint

Effect regain normal body temperature 1' ulcer with carbachol, ~ with scopolamine; histamine > than atropine I' food deprivation, 1' time to full recovery 1' myocardial necrosis with time 1' NA, adrenaline at end of rest.; > for SHR than WKY; 1,4 hr SHR still; 24 hr returned to normal; 1' corticosterone post-stress ~ ulcers in rumen during delay ~ in frequency of ulcer with T length of recovery for ulcers in corpus; opposite pattern for ulcers in remen food water consumption T in first 4 hrs then 1' at 24 hr; ambulation 1' 1 hr; $ 2 4 h r ; n o . ofboli ~ at 1 hr; body weight ~ 1, 24 hr ~, cardiolipin after 24 hr restraint with 7-72 hr daily; 96 hr values returned to normal 1' corticosterone, peak at 10 min I' corticosterone, peak at 5 min; elevated until 45 min A12(OH)z ~, ulcer when administered prior to 90 rain delay > than when given prior to restraint 1' ulcers with potency: phenylbutazone, ASA, sulfonate, 5pyrazolone, reserpine, methylprednisolone 48 hr--returned to normal free fatty acids, corticosterone normal body temperature regained 1" plasma corticosterone for 12 mo. rats; 1' NA in amygdala for 12 mo. at 6 hr; MHPG-SO4 1' only in 12 months at 6, 24 hr in hypothalamus, amygdala, p o n s + medulla reversed stress-induced receptor alterations: 1' beta adrenergic receptor binding in brain and heart; 1' alpha-1 binding in heart and vas deferens; ~ alpha-1 binding in kidney and cerebral cortex 1" in corticosterone at 1 hr maintained 24 hr; 1' in liver tryptophan, blood glucose; 5-HIAA 1' at 1 hr maintained at 24 hr Ulcer peak 2-3 hr post-stress; 84.3% healing at 48 hr Approx 83% healing at 72 hr no differences 100% healing after 4 days

Reference 48 100

140 165 212

219 218

269

275

296 359 102

68

276 345 163

358

249

364 44 213 38

RESTRAINT STRESS Shanker and Sanyal [119] suggested that banana powder exerts its anti-ulcerogenic effect locally in the gut by strengthening gastric mucosal resistance (i.e., increases the carbohydrate:protein ratio in gastric secretion and increases mucosal thickness). When these results are considered together with those of Natelson [243] showing that rats fed a tryptophan deficient diet displayed exacerbated restraint stress ulcer formation, it appears that 5-HT activity, primarily in the gut, may be an important determinant (sensitizing factor) of stress ulcer susceptibility.

349 from the conscious animal and can be left in place for as long as 6 to 12 months. An additional feature of the indwelling gastric cannulae is that they permit unrestricted access to the interior of the rats' stomachs by a fibre optic endoscopy system (Olympus NPF Type $3 nasopharyngeo fibre optic endoscope with a 5.0 mm fibre bundle; Olympus CLE-4U cold light supply). Repeated examination and photography of the glandular stomach, combined with quantitative evaluation of the extent of the gastric damage [334], can be performed in the live, but ulcerated animal. Thus, a direct and quantitative assessment of both spontaneous as well as drug-manipulated ulcer healing can be obtained.

DIURNALAND SEASONALVARIATIONS Studies concerned with diurnal and seasonal variations in restraint ulcer incidence are listed in Table 9. Most subjects used in restraint studies are nocturnal rodents and Ader's work [7] confirmed that the application of restraint stress at times when these animals are normally very active resulted in more gastric damage than when stress was applied at other times. Depending upon the response studied, especially brain amines and plasma corticosterone, the time of day at which restraint stress is applied can either mask or unduly augment the measurements in question. Very few reports of circ-annual variation in restraint stress ulcer incidence exist beyond that of Wilson [277]. It is interesting that his rodent data indicating a clear peak and trough in restraint ulcer susceptibility in December and June, respectively, parallel the seasonal trends observed in human gastric ulcer incidence and appear to be independent of environmental temperature. The reasons for such circ-annual variation in ulcer susceptibility are not known. POST-RESTRAINT/HEALINGEFFECTS Relative to the literature concerning effective and reliable ulcer production in experimental animals, far less attention has been paid to ulcer healing and post-stress effects. Two developments in this area, however, deserve mention. One development concerns the phenomenon of "poststress delay." It was reported that removing animals from a stressful situation for a 90 minute period prior to sacrifice, enhanced stress ulcer formation relative to animals sacrificed immediately upon termination of the stressor [385]. We attributed this observation to parasympathetic "rebound" activity (characterized primarily by vagallymediated increased gastric acid secretion) following a period of prolonged sympathetic arousal during application of the stressor. Data manipulating cholinergic activity [99], as well as antacid administration [102] during the "delay" period, confirmed this hypothesis. A second development concerns the study of ulcer healing. Vincent and Par6 [363] examined rats at various intervals following three hours of cold-restraint stress. It is noteworthy that even after 48 hours of post-stress recovery, 88% of the animals still exhibited an average of 10 millimeters of gastric glandular ulcers. Clearly, cold-restraintinduced ulcers do not spontaneously heal and are useful for evaluating drug effects on recovery from stress ulcer. These studies are listed in Table 10. Recently, we have obviated the necessity of sacrificing the animals in order to assess healing of ulcers at a single time point. We first implant chronic indwelling gastric cannulae into the animals [266]. This technique has been primarily used for repeated collection of gastric secretion

DRUGEFFECTS Probably the major use of the restraint stress methodology has been in the area of drug evaluation. Many of the agents listed in Table 11 have predominant actions which are anti-ulcer, antacid, anticholinergic and anti-histaminic (H1 and H2 receptor blockers) and, to a large extent, reflect the chronology of research attempts to establish effective pharmacotherapy of human gastrointestinal disease. However, many centrally-acting drugs have also been used in restraint stress research including anti-depressants, sedative/hypnotics, and anti-psychotics. Increasing interest in the interaction between stress and psychoactive drugs has most likely been prompted by recent work implicating stress in the etiology of affective disorders, especially depression [108]. A particularly interesting example of the stress-drug interaction is illustrated in a study by Tanaka et al. [344]. These workers were examining morphine effects on regional brain NA metabolism. Depending upon the environmental challenge--restraint stress or non-stressed control--morphine exerted profoundly different effects. In nonstressed rats, morphine enhanced NA release and turnover in many limbic brain structures (hypothalamus, thalamus, amygdala, hippocampus), while in restraint-stressed rats, morphine exerted the opposite effect and significantly attenuated stress-induced NA turnover in these same brain regions. Subsequently, Appelbaum and Holtzman [16] showed that restraint-stressed rats had higher tail-flick latencies than non-stressed controls and, in addition, were more sensitive to the analgesic effects of morphine. However, opiate receptor affinity (as assessed by calculation of "apparent pAT' values--the negative logarithm of the molar concentration of antagonist, naloxone, which doubles the dose of agonist, morphine, required to produce the effect) was similar in both stressed and non-stressed rats. It appears that restraint stress may enhance the release of endogenous opioids and that exogenously administered morphine augments the apparent stress-reducing effects of morphine both centrally in the form of reduced NA turnover [344], and peripherally, in the form of decreased gastric stress ulcer formation [107]. Opposite results were obtained by Nakane et al. [239] using various centrally administered neuropeptides. TRH, VIP, LHRH, and CRF produced ulcers in non-stressed rats, but none of these peptides potentiated ulcer formation in restraint-stressed rats. These studies clearly illustrate both the usefulness of the restraint methodology as well as the complexity of the interaction between stress and drug effects and emphasize the need for caution in interpretation of drug effects. The role of the central nervous system in restraint-

350

PARI~ A N D G L A V I N TABLE

11

DRUG EFFECTS

Drug

Dose

Route of Admin

Ulcer

A-Vitamin

50 iv/g

Acetazolamide Acetylcholine Aeetylmalicylic Acid

n o ~ in ulcer no effect

20 mg/kg 62.5, 125 mg/kg

t po

16, 40, 100 mg/kg 83.3, 50 mgkg

po po

2xlU

sc

and 1-glutamine ACTH

Secretion

Organ

Other

259 98 172 64

1' at highest dose dosedep T inhibited ulcer devel. 1"

254 39 259 385

50 IO/kg 1,5, 10, 20 ~,/kg

ip

gastric motility 20-50 min

440 mmol/kg

no effect reported did not promote healing

Aluminum Hydroxide Gel (Amphojel)

when administered during food dep alone and restraint no effect when admin only during restraint

Aluminum Hydroxide Gel

72, 193,238 300 mg

d-Amphetamine

100 2.5 mg/kg

po

10 mg/kg

po

J,

2 mg/kg 2 mg/kg 2ml

ip ip

J,

po

J,

Aluminum Hydroxide Gel (Basaljel) Ambutonium bromide Aminoguanidine Aminooxyacetic Acid Ammonium Chloride Amobarbital Angiotensin Apomorphine

ip po

no effect prior, > ~ post inactive t > than chlorpro.

10 mg/kg 100 mg/kg 50, 150 mg/kg

po

J,

ip sc

1.6% 50 mg/kg 0.256 mg/kg 16 mg/kg 5 mg/kg 25, 50, 100 mg/kg 100 mg/kg 100 mg/kg 100 mg/kg 200 mg/kg

po po iv

1" 150 t , 50 NS t NS~ no effect

Ref.

50 22 113

181 260 266

1' struggling behavior

68 260 317

activity 30 189 369

T t

225 30 48 129 154 193 68 30 67 80 81 115 115 115

po

t

110

500/~g %

po

no effect

Atropine

25 ~g 1 mg/kg

icv ip

$ ~,

110 157 256

Atropine methylnitrate sulfate

0,05--0.20 mg/kg 0.20-1.00 mg/kg

ip ip

ASA

Ascorbic Acid

Ascorbic Acid and nictoine

100 mgrn 30 g/1 pH 5.0 30 g/l pH 2.5 750 mg/5 1 30g/I

t sc po

dose dep 1"

po

t

po

no effect

pot ip t sc

po po po

39 39 50

RESTRAINT STRESS

351 T A B L E 11 CONTINUED

Drug

with metiamide

Dose

Route of Admin

1.2 mg/kg 0.8 mg/kg 0.8; lO0/Mkg

ip sc sc

Ulcer

Secretion

~, no additive effect

sc sc; ip sc sc;ip

additive

volume of acid

sulfate

lO;20mg/kg

20 mg J, bleeding

sulfate

and thalidomide

0.3 mg/kg 3, 10 mg/kg 5 mg/kg, 100/~g 0.3, 1, 3 mg/kg 0.8 mg/kg 0.8 mg/kg 0.2 mg/kg 1.0; 400 ~g/kg

and clonidine

1.0; 0.25 mg/kg

and chlordiazepoxide

1.0; 100 mg/kg

Bradykinin

Bretylium tosylate Brocresine Bromvalerylurea

25 mg/kg 5 mg/kg 100 mg/kg 1 p.g 0.1, 0.3, 0.6 ml 0.2, 0.6, 1.0 ml 0.1, 0.5, 1.5/xg in 10 ul veh. doses equivalent to 30 t~g of neurotensin in 10 ul vehic, equimolar to 30/.tg of neurotensin 8.0--30.0 mg/kg 20 mg/kg 150 mg.kg 250 mg/kg

1' gastric acid I' gastric acid

sc;po additive sc

~, ~, ,L $

Benactyzine Benztropine Bethanechol Bethanidine Bicuculline Bismuth subsalicylate (Pepto-Bismal) Bismuthsubsalicylate Bombesin

127 75 141 273 292 292 337 337

dose dep ~, I' T ~, additive ~,

337 339 341 secretation cholinesterase activity Brain Ca2 + no change at low dose of gastric motility either admin, route

ip sc po icv po

icy ic

gastric acid

mast cell change vasodilation no sedation

30 59 33 137 62 73 92 337

337

320

no change in body temp no change

NS

T dose dep dose dep

172 166 369 388

371

po po ip, icY dose dep. sc sc ip sc;po greater J, than when administered alone sc; sp greater ~, than when administered alone sc; sp greater J, than when administered alone

Ref. 74 74

Brain T AD, NA po

5 mg/kg 1;0.1;0.25;0.5, 1,2,4 sc 10 mg/kg sc 1.5, 3.0, 25 ~g icv, iv

Atropine + NA, Adrenaline

Other

1"

sulfate

0.5 mg/kg 0.5, 1, 2, 4 mg/kg 1.5 mg/kg 5.0 mg/kg sulfate 0.5 mg/kg sulfate & phenoxybenzamine 0.5; 1 mg/kg methylbromide 0.2; 1.0 mg/kg methylbromide & meprobamate 1.0;100 mg/kg methylbromide & bromvalerylurea 1.0; 250mg/kg methylbromide 10;40mg/kg 1; 10mg/kg

Organ

enhanced ~ body temp

141 14 256 30 157 124 123 336 156

ic

156

ip ip ip ip

48 79 histidine decarb, activity no effect

194

202

352

PARE AND GLAVIN

TABLE 11 CONTINUED

Drug and atropine sulfate Burmamide 4-bromo-3-hydroxybenzyloxyamine (histidine decarboxylase inhibitor) Caffeine

Dose

Route of Admin

250; 1 mg/kg

ip, sc

100 mg/kg 200 mg/kg

Carbenoxolone Sodium and magaldrate (Aluminum Magnesium Hydroxide)

Carrageenin Castor Oil Chlordiazepoxide

Secretion

Organ

Other

Ref. 212 30 347

~ histamine

3, 6, 12.5, 25, 50 mg/kg 100 mg/kg 0.17, 0.34, 0.5 mg. ml 140 mg/kg

ip

~'

po

I'

ip

no effect not effecttive

337 341 322

4 × 12 MRC units/kg 2 ig 0.25 mg/kg 0.75 mg/kg 100 ug/100 g 1 ml

sc icy ip

no effect no change 1" $ additive ~,

306 157 256 101,102 332 332

Calcium Carbonate

Calcitonin Carbachol

Ulcer > ~ than drug alone NS $

po

50 mg/kg po 100 mg/kg 25, 50, 100, 200 ic 100, 300 po 300 mg/kg po 10 ml/kg po 4.25, 8.5, 17 p.moles/kg ip

~ dose related t in offspring mortality

pH

NS inactive 1' ineffective in cure rate NS ineffective

cerebellar NA no effect

30 193 338 59 339 30 82

5-50 mg/kg p-Chlorophenylalanine (PCPA) 300 mg/kg

ip

6 Chloroprednisolone CCX

sc

1' no effect

39 156

ip

$

181

207,414, 689, mg/kg 245,490, 817 mg/kg 100 mg/kg 1,5, 10 mg/kg 4.0-16.0 mg/kg not indic 1,3, 10 mg/kg

ip ip ip ip ip

no effect no effect

181 181 337 160 48 141 171

75, 12.5, 10 mg/kg 30 mg/kg 1,7, 4.2, 8.5 mg/kg 2.5, 10, 20mg/kg

sc ip

CL-1700 (N-Acetyl-L-Carnosine Aluminum L-Carnosine N-Acetyl-L-Carnosine Chlorpheniramine maleate Chlorpromazine Chlorpromazine HCI

Chlorpromazine & morphine

0.5 mg/kg equimolar to 40/zg of NT 300, 600, 1000 mg/kg

10 mg/kg 10, 20 mg/kg 10, 40 mg/kg 10 mg/kg 10 mg/kg 200/~g, 20p.g

Cimetidine

20 mg/kg 10 mg/kg 40.0 mg/kg 25, 50, I00 mg/kg 25, 50, 100 mg/kg

dose dep ~,

387 30 110

sedation no change in 5-HT levels

I' blood glucose ~, $

sc

hypothalamic, telencephalic NA unchanged + at 25 J,

no change

198 234 273 273

greater ~ in NA

greater ~, at low dose ip, op I" ip J, histamine no no effect icy, iv icy ~, ivno effect po 1' po NS

high dose ~, motility

vasodilation $ po

100 ,~ ~ no dose related

$ gastric acid

92 66

317 337 338 347 172 388 352 30 73 262

RESTRAINT STRESS

353 T A B L E 11 CONTINUED

Drug

Cinchophen Clondroitine Sulfate

Dose 7 mg/100g 60 mg/kg 40 mg/kg 10 mg/kg 80 mg/kg

po

100 mg/kg 30, 100 mg/kg

po po

30, 100, 300 mg/kg 100 mg/kg 25, 50, 100 mg/kg

ip ip ip

10-300 mg/kg 20 mg/kg 100 mg/kg 100 mg/kg

po ip po

Clonidine Clotiazepam Cobaltous Chloride Cocaine Cortisone

0.256 3, 10, 30, 100 mg/kg 45 mg/kg 20 mg/kg 5 mg/kg 75 mg/kg deoxycorticosterone, cortisol 2 mg; 100 ug parathyroid extract 125 USP 1, 5, 10 mg/kg

Cyproheptadine

Route of Admin

1 ug 30 mg/kg 5 mg/kg

Ulcer

Secretion

Organ

Other

pH '~

332 193 240 369 245

1` ip sc po

gastric acid 1` serum ~, ½ vaggastrin otomy > alone NS ~, ~ in one study not in another dose dep ~, no effect 1' pH ~ at all doses dose dep ~,

30 59

137 247 266 no sedation no sedation

~, ~" not effective

iv dose dep ,L sc ip sc sc

1" stomach GSH no effect ,L J,

$ mortality

icv sc ip

340 92 80 172 341 45 137 42 154 39 259 311 385

$ gastric motility 20-50 min

ip

Ref.

157 30 33

no effect no effect 20-50 min

2-deoxy-D-glucose

Depensen (XN-263, anti-peptsin)50, 100, 200, 400 mg/kg ig Desmethylimipramine HC 1

Dexamethasone Diazepam

desmethyl diazepam 3-hydroxy diazepam

dose dep 1"

10, 50, 100, 200 mg/kg sc

3, 10, 30 mg/kg 10 mg/kg 25 mg/kg 10 mg/kg 0.02 mg/kg 1,5, 10 mg/kg

sc ip ip ip sc sc

4.5, 9, 18/xmoles/kg

ip

Diazoxide Dibenzamine

4.75, 9.5, 17 p.moles/kg ip 4.25, 8.5, 17 p.moles/kg ip 2.5 mg/kg ip 25 mg/kg 256.0 mg/kg ip 50, 100 mg/kg

Dibenzyline Dichloroisoproterenol Diclofenac 5, 6, dihydroxytryptamine Dilospan (COMT inhibitor) Diphenmethanil Diphenylhydantoin DMBA Disulfiram

10 mg/kg, 700 p.g 32.0 mg/kg 5 mg/kg 5, 10, 20 mg/kg 75 mg 150 mg/kg 6 mg/kg 98, 146/~moles/kg 5 mg/g 100, 200, 400 mg/kg

Slight increase in gastric motility

192

J, 100, 200 400 hypothalamic NA immobility in chronic restraint, no change in body temp. not noted Hypothal. NA attenuated dose dep ~[ CerebeUar NA slightly dose dep no effect

no effect, J, 100rag

82 82 82 164 45 341

$ MHPG-SO4, NA

partially blocks motility dose dep 1'

ip iv ip

J, hypothermia between 45-120

NS ineffective

cerebellar NA J, J, turnover induction

at 400 mg

171 272 14 105 36 166 171

ip, icv iv sc icy sc

179

33 45 51 193 14 166 141 82 247 78

354

PARE

TABLE

AND

GLAVIN

11

CONTINUED

Drug Domperidone

Dose

Route of Admin

Ulcer

1 mg/kg 1 mg/kg 30, 60, 240 mg/kg

ip sc

50 mg/kg l0 mg/kg 40 mg/kg 25 mg/kg 20, 40 mg/kg 0.16 mg/kg 200 mg/kg 0.5, 5 t~g 1, 10/zg 1, 10p.g

sc sc ip

i, 10 p.g 1,10 p.g

icv icy

100, 200 p.g

icv

100, 200/~g in 10/x 1 vehicle equal to 30/~g of NT

icv ic ic ic

Epinephrine

0.1 mg/kg

ip

sc

~

Estradiol Benzoate Estrogen Ethanol

0.1,0.25,0.5,12,4 mg/kg 25, 50 p.g 5 mg/kg 10, 25, 35, 50%

sc ip po

Ethylestrenol FLA-63 (DBH inhibitor)

10 mg/kg 25 mg/kg

po

~ no effect greater 1' with prestress administration greater with poststress administration ~

Fluphenazine

0.001-10 mg/kg

ip

L-Dopa

Dopamine

Doxepin Isopropamide Emilcamate and isopropamide B-Endorphin

leu-Enkephalin

met-enkephalin met-enkephalin leu enkephalin B-endorphin

FPL-52694 (most cell stabilizer) G.31 002 (Methaminodiazepoxide: Reserpine) Gastric Juice (Artificial) Oastrin

Garanyl farnesyl acetate

sc po icy icv icv

Secretion

Organ

~, no effect 30 ~,, 60 1', 2401' NS ~, NS ~, ~, J,

enhances the body temp ~ no effect on brain NA attenuated stress 1' in MHPG-SO4 all regions no effect attenuated stress ~" in MGPG-SO4 in hypothalamus, amygdala, hippocampus attenuated stress 1' in MHPG-SO4 hypothalamus, amygdala,h.ippocampu s attenuated stress 1' in MHPG-SO4

166 166 175 129 193 172 337 336 346 346

346 346

346

all regions no effect no effect $ at low dose

156 156 156 ,~ gastric motility completely 70-120 rain

204 t3 169

~, at0.01 and0.1 mg 1" at 5 and 10rag

po

J,

5, 10, 20 mg/kg

sc

no effect

30 125

160 340

dose dep 36 no effect on gastric bleeding

no effect

383

48

~ NA, adrenaline; NA more in all regions

ic

Ref. 84 154 129

J, greater ~ dose dep ~

10, 100, 200 mg/kg

in 10/xl equimolar to 30/~g of neurotensin 50-70 mg/kg

Other

371 156

227

RESTRAINT STRESS

355 TABLE 11 CONTINUED

Drug

L-glutamine and acetyisalicylic acid and taurocholic acid Glucose Guanethidine Sulfate

Haloperidol

Heroin HCI acid

Dose

Route of Admin

Ulcer

I00, 200 mg/kg ig, sc 50-200 mg/kg 83.3,250 mg/k8 po 750 mg/kg po 750 mg/kg po 15% solution po 0.5, 1.0, 2.5, 5.0 mg/kg ip 30 mg/kg ip

allinactive ~ ~ ~ ~ ~

100 mg/kg 5 ~g 0.03, 0.02, 1 mg/kg

po icy sc

NS ~, no effect

I mg/kg 0.1, 1.5 mg/kg 0.03, 0.06, 0.12 N

ip ip ig

no effect

Secretion

Organ

Other

10% mortality J, latency to t gastric motility

Ref. 314 227 254 254 254 310 34 385 30 157 171

hypothalamic, telencephalic NA no change body temp ~ ~ atlow

84 208 244

dose; t at

HCI acid and Pepsin Hexamethonium Hexobarbital Histamine

2 ml 30 mg/kg 20 mg/kg 10o mg/kg 0.4, 2, 4, 8 mg/kg 4, 8, 16, 32 mg/kg 0.1, 0.5, 1.0, 10, I, 5-2000 mg/kg/24 hr

high dose no effect ~ ~ ~

PO im

po sc iv

dose dep 1'

iv

Peak HCI response at 100 mg

10 mg/kg 5 ml

~ ip

Hydergine

im

Hydrazine-phenyi-isopropyl aHydrazinohistidine

500 Izg 200 mg/kg

ip ip

6-Hydroxydopamine

less ~ inbodytemp less t inbodytemp urinary Adrenaline ? ~,

100/zg

icv

25 mg/kg 200 mg/kg 200 mg/kg

sc

250 mg/kg 25, 50, 100 mg/kg

ip sc

t

l-isoleucine Indomethacin

2.5, 5, 10mg/kg

no effect no effect

no effect on corticosterone

no change brain catecholamines

29% cure rate

~, icv

po

sc

no change in body temp t corticosterone

~ 10, 20 no effect on adrenals

33 339

295 14 281 30, 199 234 36 235 193

dose-dependent ?

t t

337 79 281

166

~, gastric blood flow

t gastric bleeding

lO m~/~ 5 mg/kg

99

brain catecholamines, J, 5-HT

ip ip sc po

95 127

250

no effect on 5-HIAA or 5-HT

60 mg/kg

5, 6-Dihydroxytryptamine Imipramine HCI

greater 1' with restricted diet

slight ~

95 95

33 347

~ histamine sc

50 mg/kg 100 mg/kg 50/~g 3 mg/kg 30 mg/kg 5, 10, 20 mg/kg 4-7 g/kg

356 ~,

2mg/100g 0.6mg/100g 1 mg/kg

Hydrocortisone

No change in gastric motility

~ 1'

341 30 341 30 179 34 356 180

37l 3O 155

356

PARI~ AND GLAVIN

TABLE

11

CONTINUED

Drug

Indoramin Iproniazid

lsoprenaline Isopropamide and clidinium

Isoproterenol

Ketamine Kompenaan-S-liquid (Antacid) Levodopa Lidocaine Lorazepam Lysergic Acid Diethylamide Magaldrate Magnesium-aspartatehydrochloride Magnesium trisilicate Mecamylamine HC1 Mepiperphenidol Meprobamate

Mepyramine maleate

Methacholine Methaminodiazepoxide Methyltyrosine

Dose 5 mg/kg 5 mg/kg 40 mg/kg 30 mg/kg 150 mg/kg

Methylphenidate

iv ip ip

Ulcer

],

100 mg/kg 0.04, 0.4 mg/kg 5 mg/kg 10 mg/kg

slight 1' ~ J, greater ~ in combination than alone

5 mg/kg 16.0 mg/kg 16.0 mg/kg 5 mg/kg 0.5, 2.5, 5, 10 mg/kg 6 mg/kg 75 mg/kg 600 mg/kg 1000 mg/kg 10 mg/kg 3 mg/kg 0.25-2.5 mg/kg 0.1-1.0 1 ml 194 mg/kg

ip

Secretion

Other

ip sc po po ip sc

no effect on adrenals 1' brain catecholamines

], cholinesterase activity

56 193 121 30 30 92 48 332 216

slight j, slight "~

I"

sc po po ip ip ip

6.25,25 mg/kg 6.3, 25 mg/kg 30 mg/kg 10 mg/kg 4.0 mg/kg 5, 10, 20, 50 mg/kg 80 mg/kg

~, ],

J, intestinal flora ~,

ip po

NS ~,

sc

],

im im

dose-dep ~ noeffect

iv

no effect on hydrothorax 3-4 fold 1" in stomach hexosamine content

attenuated the 1' in brain catecholamines MHPG-SO4 levels, ~' NA levels 1" MHPG-SO4 dose dependent in hypothalamus, midbrain

sc sc

3 mg/kg

sc

$

4-7 g/kg 200 mg/kg

histamine no effect

icv ip

$ $

105 178

30% cure rate no effect on adrenals

30 30 48 141 337 352 341 48 30 287 286 62 61 30 33 45 36 375

slight no effect no effect no effect

ip

2, 5 mg/kg

166 30 90 172 337

256 45 101 166 144 197

1' slight dose-dependent T 200% 1' I'

~,

Ref. 246 84 80 30 347

sc iv

2 g/kg 5 mg/kg 5.0-20.0 mg/kg 24 mg/kg 100, 200, 300 mg/kg 150 mg/kg 300 mg/kg 100-500 mg/kg 150mg/kg 1,3, 5 mg/kg 2.5 mg/kg

40 mg/kg 80/xg 5 mg/kg

Organ

1' T I' ~

50 mg/kg

Methamphetamine

Methaxamine D-Methionine DL-methionine Methyl dopa

Route of Admin

330 236 347 79 157 154

RESTRAINT

STRESS

357 TABLE

11

CONTINUED

Drug Methyl-Prednisolone Methysergide Metiamide

Milid Milk: cream (1:1) Milk: corn oil (1:1) Milk Morphine

Naloxone

and morphine and heroin

Nerve Growth Factor Neurotensin

Nicotinic Acid

Nitrazepam Noradrenaline

Dose

Route of Admin

2.5 mg/kg 1 ptg 100 mg/kg 0, 20, 40, 80 tzmol/kg 2.44, 4.85, 9.76 mg/100 g 25, 100 mg/kg 100, 400 izmol/kg 100 mg/kg 5 mg/kg 25, 100 mg/kg

Ulcer

Secretion

1, 2, 4 mg/kg 5.0-20.0 mg/kg 5, 15 30 mg/kg 2.5-20 mg/kg

po 1" icy no effect po 1" ig ip J, at higher doses ip sc po slight ,L ip dose depen- dose-dependent $ dent sc inactive no effect no effect no effect at4mg ip ip not active ip sc

3.6 mg/kg 10 mg

sc icv

3 mg/kg

po

200 mg/kg

0.1 mg/kg

sc

1 mg/kg

ip

2 mg/kg 12.5, 25, 50 mg/kg 5 mg/kg 30 mg/kg 5 mg/kg 0.1-5 mg/kg 1.5 mg/kg

ip ip

0.5, 5 mg/kg 5 mg 7/zg 30/zg 10, 30, 100/.tg

sc

J,

Other

no effect

body temp temp at 20 rag; 1' temp at 2.5 and 10p.g; ~, with stress attenuated stress 1" in all regions for MHPG-SO4; dose dependent 1" in MHPG-SO4 in hypothalamus, amygdala, thalamus, hippocampus, midbrain; ~, NA in hypothalamus, amygdala, thalamus, MHPG-S04 hippocampus T in whole brain

no effect all doses 1' ~, body temp blocked ~, body temp blocked body temp blocked Antagonized J, in body temp ], hypothalamic NA, T HGPG-SO4 1' MHPG-S04 MHPG-SO4

ip

sc

NS

Ref. 67" 157 3O 50 36 61 74 30 33 62

blocks stress-induced reductions of investigatory behavior prevents hyperprolactinaemiainduce hypothermia

po I' two-fold ic $ ic, icv dose-dependent ~, greater at 30 ~g icv no effect 5/xg 5, 10, 15, 20, 25, 30/xg ic dose-dependent sc J, at all 8, 16.6, 36.2, doses 62.5 mg/kg po 500 p.g % ip ineffective 8.9, 17.8, ttmole/kg iv no effect 0.016, 0.256 mg/kg ip 0.1 mg/kg 0.1, 0.25, 0.5, 1.0, 2.0

Organ

344 346

30

178 20

84 157 108 208 208 208 367 342 344

ic effective; iv ineffective

no effect on body temp

gastric motility

192 22 22 22 106 48 208 357

197 256 248

336 32

111 198 45 385 166

358

PARE AND GLAVIN

T A B L E 11 CONTINUED

Drug

Olive Oil Ornithine Oxazepam

Oxybenzamine HCI Oxyphenonium Bromide Papaverine HCI Para-DL-chlorophenylalanine (PCPA) Pargyline HC1 PCPA-methylester Pentobarbital Sodium Pentagastrin PGEe (16, 16 dimethyl)

Phenobarbital

Phenobenzamine Phenoxybenzamine

Phentolamine Phentolamine HC1 Phenylbutazone

Phenylophrine Phosphoryloline Pilocarpine Piparoxan Substance P

Pirandamine HCI

Pirenzepine Polyamine B Practolol

Dose

Route of Admin

Ulcer

mg/kg 1 mg/kg 10 mg/kg

ip po

~

8.75, 17.5

ip

noeffect

30 mg/kg 20 mg/kg 0.33 mg/kg 75 mg/kg 250 mg/kg

po ip sc ip ip

slight $ ~ J, slight $

100 mg/kg 50 mg/kg 100/zg 20.0--45.0 mg/kg 30 mg/kg 5, 100 ~g/kg

ip

Secretion

Organ

Other $ O2 consumption by 56% 39% cure rate

icv ip ip sc

3-10 t~g/kg

sc

1, 2 mg/kg 0.5, 1, 2, 4 mg/kg/min 10 tzg/kg 0.1, 0.3 mg/kg 40 mg/kg 10, 30, 90

ig sc sc po

no change in body temp

no effect on histamine

hypothermia

dose dep ~

Inhibits gastric motility

10 mg/kg

im

10.0 mg/kg 30.0 mg/kg 10.0 mg/kg 15 mg/kg 1 mg/kg 125 mg/kg 200 mg/kg 50, 100 mg/kg 50 mg/kg 100 mg/kg 200 mg/kg 10 mg/kg 0.1 ml/min

ip po im ip

no effect no effect

ip po po

T 1'

no effect

urine NA, adrenaline 1'

127

I" vasodilation ~

1' 1' 1 1' ~ no effect on acetylcholine turnover 1"

icv no effect ~ atlow dose ~ ip ~ 5 ~ ,dosedependent 1" po dose dep ~ po ~ po ,[ po 1"

~ NA, adrenaline, in all brain regions

J, ~

+ gastric acid

14 48 30 179 244 371

234 30 58 258 125

NA no change slight ~ adrenaline

po

30 79 317 337 345

192 192 371 371 337 171

dose-dependent in hypothalamic, telencephalic NA no effect slight $ ~ ~

128 30 339 82

171

1' dose-dependent J, inactive J, ], I" no effect

po iv ip

7.5, 10 mg/kg 10, 20, 40, 80 mg/kg 6 mg/2 ml 26 mg/100 ml 10 mg/kg

hypothalamic, telencephalic NA 1"

not active slight $

100 mg/kg 50 mg/kg 1 mg/kg 5 mg/kg 5 mg/kg

20 mg/kg 60 mg/kg 5 tzg 4.5, 9, 13,54, 8.3, 77.7 txg 3 mg/kg 3 mg/kg 1,5, 150p.g

slight ~ cerebellar NA

Ref.

166 29 73 79 341 80 67 64 172 30 68 166 53 172 125 336 156 199 199 33 193 75 292 124 30

RESTRAINT STRESS

359 T A B L E 11 CONTINUED

Drug

Dose

Route of Admin

Ulcer

Prazosin

10 mg/kg

Predmsolone

I mg/kg 10 mg/kg 0.5, 1, 2, 3 mg/kg

sc sc

~,

methyl-prednisolone 6-ehloroprednisone Prednisone

2.5 mg/kg 0.5 mg/kg 4 mg/kg I, 2.5, 5, I0 mg/kg

po sc sc sc

t

Probanthine Probenecid

0.45 mg/kg 200 mg/kg 200 mg/kg

sc

125 mg/kg

ip

30 mg/kg 125 mg/kg 10 mg/kg 250 mg/kg 1, 2, 4, 8 mg/kg

po

NS~

ip po ig

no effect

Proeainamide 17-OH Progesterone Progesterone Proglumide Pro-Pantheline Propentheline Propyldoacetamide (H-2254) Propranolol

Propranolol (dl)

Prothipendyl

Pyrilamine maleate Quinacrine Ranitidine Reserpine

Reserpine phosphate

500 mg/kg 12 mg/kg 10 mg/kg 10 mg/kg 1, 5, 10 mg/kg 2.5 medkg 0.5 mg/kg 5, 10, 20, 50 mg/kg 5, 10, 20, 50 mg/kg 30-60 mg/kg 0, 20, 40, 50/~mol/kg 10-100 mg/kg 60 mg/kg 1 mg/kg 0.60, 0.2, 2 mg/kg 50 mg/kg 0.06,0.1,0.75, 1.0 25 mg/kg 0.5, O.1 mg/kg 2.5 mg/kg 0.025, 1 mg/kg 0.1 mg/kg I mg/kg

Secretion

Organ

Other

~ NA, adrenaline in all brain regions

125

,~ time for recovery no effect on hydrothorax

~

~

101 222 343

t 5-HIAA in brainstem, no change 5-HT t 5-HIAA hypothalamus,thalamus, amygdala, hippocampus, cortex, ports + medulla t PGE2,F2a

ip

32 30 259 13 255 192

mg

141 66 256 166 30 314

no change in 5-HT ip

no change

ip

slight

po ip

slight ~,

no effect on plasma renin

im ip

vasodilation-no effect

io, 50 sc ,. tp

J, at 50 and 20 m g not active

no effect on histamine no effect

po

t

75 121

T

ip ip ip sc

73 292 317 36 48 50 347

no effect

po ip sc

39 141 287 59 39 39 155

not noted dose-dependent ~,

~ at2,4,8

ReL

mortality 40% t

gastric motility

t

t $ NA prevented adaptation, to restraint--50% mortality no effect on histamine shortened latency to t gastric motility

2.5-10 mg/kg 2.5 mg/kg

ip

15 mg/kg

ip

1'

8 mg/kg 0.05, 0.I, i mg/kg

sc

5 mg/kg 2.5 mg/kg

po sc

t at all doses t slight

gastric blood flow

67 34 35 40 64 142 29O

347 385 172 175 36 66 30

360

PARI~ A N D G L A V I N

T A B L E 11 CONTINUED

Drug

Dose

Retinol 50-200 mg/kg Ro- 15-1788 (Ethyl 8-fluoro-5, 5, 10 mg/kg 6-dihydro-5-methyl-6-oxo-4Himidazo-(l, 5-a) (1, 4) benzodiazepine-3-carboxylate) and diazepam Salbutamol 0.04, 0.4 mg/kg Saline 0.25 ml/100 g Sch 28080 (2-methyl-83, 10 mg/kg (phenylmethoxy) imidazo (1, 2-a) pyridine-3-acetonitrile) Scopolamine methiodide 1.5 mg/kg 1.0 mg/kg Scopolamine methylbromide 0.02-0.20 mg/kg 1 mg/kg Semicarbazide 50 mg/kg 150 mg/kg SK (P64139 (phenylethanola40 mg/kg mine-N-methyltransferase Sodium Bicarbonate (15%) 2 g/kg 2 g/kg 0.9%, 1.3%

Sodium Nitrate Sodium sulphate (3sSlabel)

Sodium taurocholate Somatostatin

Somatostatin Sotalol Spiroperidol Sucrose Sustagen

Route of Admin

Ulcer

ip

ip sc po

Organ

ip ip

~' NA in hypothalamus, amygdala hippoeampus, cort, pons& reed cerebral cortex, p o n s + medulla

~ ~, ~,

$ ~ ~ ~ ~ ~

Other reversed effect of diazepam

po

~

po ig

~ dose-dependent 3' no effect ~

6%, I ml 64 mg/kg 100/~curies

po iv ip

100 p.curies 500 mg/kg 5/~g 4.9, 9.7, 14.5, 19.6 24.5, 29/zg 30 p.g 250 mg 15 mg/kg l, 5, lO mg/kg 20 g/IO0ml

ip po ic ic ip ip ip

~ gastric tissue histamine

25% mortality 3, incorporation of radiosulfate in gastric mucosa

hypothermia

no effect ~ at 5 and 10

T blood glucose Significantly promotes ulcer healing

PO po ip po

1' $ 3,

Taurocholic Acid Tetrabenazine

30, 100, 300 mg

po

10 mg/kg 5 mg/kg 25 mg/kg 5, 10, 20 mg/kg 5, 6 mg/kg 1, 5, 10 mg/kg 2 mg/kg 5 mg/kg

ip ip sc ip ip ip ip

dose-dependent 1" I'

Tetragastrin Thioproperazine Thiopyrano (3, 4-b) indoles Thioridazine Thiosemicarbazide Threo-dl-p-hydroxymethylphenidate Thyrotropin releasing hormone equal 30/zg NT 5 p~g 50 mg/kg Tiotidine 1 mg/kg Tolazoline 25 mg 30-60 mg/kg 250 mg/kg

~ prevent NA ~ in adrenale

141 102 48 101 283 369 125

62 45 167 196 30 336 156 246 210 314 160 112 22 68 339 199 236 254

3, 1' blood glucose

'~ icv no effect po no effect no effect

ip ip

no effect no hypophysectomized animals

1" cotlogenas¢ activity no effect 3, ~, ~ ~

227 164

135 339 30 244

T no effect ~ at low dose no effect

700 mg/kg 2 g/kg 2 mg/kg 4-7 g/kg

Ref.

90 214 59 59

~ adrenaline in all regions

Sulfonate-5-pyrazolone Synthetic aluminum silicate Tandamine HCI Taurine

Tranylcypromine Trifluoperazine HC1 methyl-Tyrosine

Secretion

~

hypothermia

3, gastric bleeding no effect on histomine in brain NA, DA

172 87 255 36 199 160 240 154 156 336 75 341 371 347 48 66

RESTRAINT STRESS

361 T A B L E 11 CONTINUED

Drug

Dose

Route of Admin

Ulcer

Organ

Other Attenuates restraint-induced corticosterone elevations

Tyrosine

0.92% of diet

po

Urea

Vasopressin Verapamil

60 mg/kg 0.5, 2, 8 mg/kg 1 mg/kg 1, 2, 4 mg/kg

iv no effect iv no effect ip ~, ip dose dep

VIP Zinc Sulphate

equal 30/~g NT 22, 44, 80 mg/kg

T dose dependent po dose dependent

1, 11, 22, 44 mg/kg

Secretion

plasma gastrin stomach contraction; inhibits mucosal mast cell degranulation

278 30 45 367 253 156 66

ip

induced gastric disease has been investigated by a n u m b e r o f researchers. M o r e recently, as a result o f the w o r k o f H e n k e [153], the a m y g d a l a has been implicated in restraint ulcer. H e n k e o b s e r v e d that gastric erosions w e r e p r o d u c e d only w h e n stimulation was applied to the central nucleus o f the amygdala, thus leading H e n k e to conclude that this amygdala area r e s p o n d e d to the emotional c o m p o n e n t o f restraint stress. H e n k e has c o n d u c t e d considerable research on this topic, and the serious student or r e s e a r c h e r interested in brain-gut relationships should o f necessity b e c o m e familiar with H e n k e ' s e x t e n s i v e and interesting r e s e a r c h [145-153]. We h a v e r e v i e w e d and compiled an e x t e n s i v e bibliography on the m e t h o d o l o g y , salient features and primary applications o f restraint stress. We suggest that these techniques, if used after careful consideration is given to choice

Ref.

fragility of lysosomes in gastric mucosa

63

o f sex, strain, species, age, method, duration, time of day/year, and diet, can be powerful, valid, reliable, and reproducible models of stress response s y n d r o m e s . Such synd r o m e s include peripheral gut disease, h o r m o n e and peptide dysfunction, as well as central n e u r o c h e m i c a l aberrations. In addition, since m a n y p r o v e n therapeutic agents are also active in restraint stress-induced models o f disease, we suggest that these models have a valuable role to play in drug screening and d e v e l o p m e n t .

ACKNOWLEDGEMENTS We thank Kate Kiernan, Carroll Powney and Betty Fayer for technical assistance.

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363

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