- Email: [email protected]
Reduction of stomach ulceration by hypothalamic stimulation in the unrestrained rat
Physiology & Behavior, Vol. 16, pp. 391--393. Pergamon Press and Brain Research Publ., 1976. Printed in the U.S.A.
Reduction of Stomach Ulceration by Hypothalamic Stimulation in the Unrestrained Rat' JOHN MARSHALL 2 AND BRUCE MCCUTCHEON a
Psychology Department, State University o f New York at Albany, Albany N Y 12222 (Received 18 July 1975) MARSHALL, J. AND B. MCCUTCHEON. Reduction of stomach ulceration by hypothalamic stimulation in the unrestrained rat. PHYSIOL. BEHAV. 16(4) 391-393, 1976. - Gastric lesions were produced in unrestrained rats subjected to a 6 hr shock stress session followed by a 2 hr rest period. Electrical stimulation of the brain (posterior lateral hypothalamus) administered during the 2 hr post stress rest period significantly decreased ulcer development (i.e., percentage of animals showing lesions, number of lesions per animal, and severity of lesions) in the test group. ESB
Ulcers
Stress
Rat
ELECTRICAL stimulation of the hypothalamus has been shown to counteract a number of behavioral and physiological manifestations of aversive stimulation [3, 7, 9, 18]. Freimark [7], for example, showed that electrical stimulation of the posterior, lateral hypothalamus (a well-known rewarding stimulation area) reduced the severity of stomach ulceration caused by pain induced stress in rats. The design of his study called for rats to receive 1 to 5 randomly scheduled footshocks during a 50 min session in which they bar pressed for food. After 19 or 29 sessions, these animals developed significant stomach ulceration. They could be protected from this ulceration, however, by giving them I00, randomly scheduled 0.5 sec bursts of hypothalamic stimulation throughout each 50 min session. An important implication of this study is that the rewarding nature of the brain stimulation interfered with the development of the fear engendered by the unavoidable foot shock. The mechanism of this interference may result from a direct blocking of pain perception [ 12,18] or from blocking the formation of an aversive, stressful motivational state (fear) which would accompany anticipation of painful stimulation. Another quite different mechanism may account for the p r o t e c t i v e effect of hypothalamic stimulation. Such stimulation may have a direct effect on the physiological parameters of gastric activity which would counteract the irritative stress reaction in the stomach. Hypothalamic stimulation in both anesthetized and awake animals has been shown to produce marked changes in stomach acidity [2, 5, 10]. Although stomach acidity level has not proved to be a reliable correlate of acute ulceration [ 13,14], it is
possible that some other critical gastric physiological process is also affected by hypothalamic stimulation. Desiderato, et al. [4] employed an experimental design which can help separate the possible mechanism of fear reduction from the mechanism of direct antagonism of stomach ulceration. They found that pain stressed rats ulcerated much more severly if allowed to rest 2 hr in the safety of their home cage after a 6 hr random, unavoidable foot shock session than rats simply kept in the stress session for 8 hr. They suggested that the explanation for this result was that in the safe home cage there would be a strong parasympathetic rebound which would aggravate an ulceration process. Since lateral, posterior hypothalamic stimulation has been shown to produce sympathetic activation [6, 16, 17], we predicted that we could obtain a significant reduction in ulceration by providing the stressed rats with posterior hypothalamic stimulation while they rested 2 hr in a safe cage immediately following the stress induction session. This design thus allows us to examine the influence of hypothalamic stimulation on ulcer formation without altering pain or fear perception during the foot shock session itself. We report, in fact, that in many cases hypothalamic stimulation can completely protect the test rats from ulceration. METHOD
Animals Sixteen male6 Long Evans rats (Blue Spruce Farms), approximately 180 days old (300g), were individually housed in a temperature and humidity controlled room
1This research was supported in part by an Institutional Biomedial Research Grant to the Psychology Department. 2Predoctoral fellow, now at Albany Medical College, Albany, N.Y., 12208. 3Send reprint requests to second author. 391
392 with a normal 12 h r - 1 2 hr l i g h t - d a r k cycle. Approximately 3 weeks prior to testing, the animals were put on restricted diets which reduced their body weight to approximately 75% of their free feeding weight and maintained them within a 2 2 5 - 3 4 0 g range. All animals were food but not water deprived for a 48 hr period prior to the stress procedure. The experimental session ran from 800 hr to 1600 hr during the light period.
Apparatus The shock apparatus consisted of a 90 × 30 × 35 cm Plexiglas chamber which rested on an elevated grid f l o o r made of stainless steel rods 2 cm apart. Programmed electrical shock was automatically delivered through the grid from a Foringer Shock Power Supply unit (model 1154MII) and Foringer Grid Shock Scrambler (model 1925). Electrical stimulation of the brain (ESB) and rest treatments were administered in another room while animals were in a 50 x 40 × 50 cm Plexiglass chamber with solid floor. Brain stimulation was delivered by a 60 Hz AC stimulator. The duration was 0.5 sec and the rate was between 25 and 35 stimulations per min. All animals were unilaterally implanted with 0.5 mm dia. bipolar electrodes (Plastics Products Company, MS 303-.018-.312-SS.008). Surgery was performed under pentobarbitol anesthesia (60 mg/kg). All electrodes were aimed at the posterior aspect of the lateral hypothalamus. The DeGroot coordinates were: 1.5 mm lateral to midline, 1.6 mm posterior to bregma and 8.5 mm ventral from the surface of the cortex [ 15]. After 2 weeks of postsurgical recovery, the rats were tested for rewarding effects of electrical brain stimulation. At least 3 separate 1 hr tests were employed to make this assessment. An optimal current level as well as an average rate of bar pressing were determined for each animal. Only those animals that maintained an average rate of at least 350/15 min for hypothalamic sites were used in the test groups. Control group animals were those rats that did not show sufficient bar pressing behavior during the 3 test sessions (less than 25/15 min). The stress procedure, which was similar to that used by Hamilton and Katske [81 as well as Wald, MacKinnon and Desiderato [20], was carried out in the following manner: 2 food deprived rats, 1 experimental and 1 control, were each placed in a shock chamber and for the first 2 0 - 3 0 rain given only fixed interval shock alternating from one side of the grid floor to other side every 40 sec. Shock duration was 2 sec and shock intensity was 0.4 mA. After this initial period during which both animals learned to consistantly escape the shock by running to the opposite nonshock side of the grid floor, a discrete 2 sec duration shock was introduced to the safe side of the grid on a 50 sec variable interval schedule. At this point the current intensity was raised to 0.8 mA. The most common behavior of the rats to the unpredictable shock on the safe side of the grid was to run to the opposite shocked side of the chamber, and then to run back to the safe side and wait for the possible reoccurrence of the variable interval shock. After this 6 hr stress treatment, the experimental and control animals were removed from the shock apparatus and each placed in a plastic chamber, located in another room, where the experimental rat received 2 hr of automatic ESB and the control rat rested (no ESB) for 2 hr. Current intensity and delivery rate of ESB stimulation were the same as used to obtain the optimal rate of self-stimulation. On the average, the experi-
MARSHALL AND MCCUTCHEON mental rats received about 25, 0.5 sec bursts of stimulation per min at about 35 ~amps. No food or water was available during this period. Immediately following this 2 hr period, all animals were deeply anesthetized with 60 mg pentobarbitol for stomach removal and brain perfusion with 0,15 M NaC1 and 10% Formalin. The brains were removed and kept in 10% Formalin for 1 week. They were then cut into 40 ~ frozen section, stained with cresyl violet and examined for electrode placement. The stomachs were opened by an incision from the pylorus to the esophagus along the greater curvature and turned out for examination. The extent of the pathology, which was almost invariably restricted to the glandular portion of the stomach, was determined by quantifying the size and number of bloodfilled lesions using a 15 × binocular dissecting microscope and millimeter ruler. RESULTS The evaluation of gastric pathology consisted of: (1) the percentage of animals per group that exhibited ulcers, (2) the number of ulcers seen in each animal, and (3) ulcer severity as determined by weighted score based on the measured length of lesions in mm. The score given each ulcer was determined by applying an ulcer index to lesions of varying size. Lesions under I mm received a value of 1, those between 1 and 2.9 mm a value of 2, those between 3 and 4.9 mm a value of 3, and those over 5 mm a value of 4 [4]. The contents of Table 1 show the ulceration present in each animal in both groups. A significant difference was found between the mean number of ulcers in the 2 groups (t = 4.0, d.f. 14, p<0.01). Ulcer severity, as recorded by the ulcer score, was also found to be significantly higher in control group rats than in experimental rats, (t = 4.5, d.f. 14, p<0.01). Table 1 shows the comparison of ulceration indices between animals receiving ESB during the 2 hr post stress period and those allowed to rest during this period. Five rats in the experimental group showed no evidence of ulceration and little, if any, stomach irritation. Electrode placements were histologically determined for 7 out of 8 self-stimulating rats. Six animals had electrodes in the region of the MFB in the posterior lateral hypothalamus and I animal had the electrode in a more posterior location near the substantia nigra.
DISCUSSION Hypothalamic stimulation greatly reduces the incidence of gastric ulcers in active rats following relatively short stress treatment. The experimental procedure results in ulcer reduction without direct modification of the footshock stress period by the brain stimulation. Although most early attempts to explain the formation of stress induced gastric lesions were based on an increase in gastric acid secretion [ 11,21 ], more recent findings have not supported the hypersecretion hypothesis [1, 13, 14]. Perhaps a more helpful way of explaining the mechanism behind ulcer formation following stress would be in terms of the relative activity of the sympathetic and parasympathetic autonomic system responses and the known vascular and hormonal changes associated with them [ 6,17]. Situations that would tend to increase parasympathetic responses following high sympathetic activity, such as the immediate return to a safe
393
R E D U C T I O N O F U L C E R A T I O N BY S T I M U L A T I O N TABLE 1 ULCER FORMATION IN EXPERIMENTAL AND CONTROL GROUPS
Group Stress and ESB
Rat No. 1 2 3 4 5 6 7 8
0 2 0 2 0 0 2 0 0.75
9 I0 11 12 13 14
3 6 5 3 2 10
Mean Values Stress and Rest
15 16 Mean Values
No. of Ulcers
7 3 4.8
Size of Ulcer (mm) 0 1, 1 0 <1, <1 0 0 1.5, <1 0 0.83 (2)1, 2"t (6)1 (4)1, 2 (3)1 4, 1 (5)1.5, (3)1 (2)2 (4)1, (3)2 2, (2)1 1.3
Ulcer Body Weight Score* (g) 0 4 0 2 0 0 3 0 1.1
240 280 300 300 240 335 270 285 281
6 12 10 6 5 20
225 300 220 240 270 340
14 6 9.8
315 225 266
e n v i r o n m e n t f o l l o w i n g s h o r t - t e r m s h o c k stress, m a y b e p a r t i c u l a r l y effective in p r o d u c i n g r a p i d a n d severe ulceration. Conversely, t h e m a i n t e n a n c e o f high s y m p a t h e t i c a c t i v i t y f o l l o w i n g stress t e r m i n a t i o n m a y h a v e a n o p p o s i t e effect. Since s t i m u l a t i o n o f t h e lateral h y p o t h a l a m u s h a s b e e n k n o w n t o p r o d u c e s y m p a t h e t i c - l i k e r e s p o n s e s in t h e g a s t r o i n t e s t i n a l t r a c t [ 6 ] , in the c a r d i o v a s c u l a r s y s t e m [ 1 6 ] , a n d in t h e a d r e n a l s y s t e m [ 1 7 ] , it m a y b e t h a t t h e p r o t e c t i v e n a t u r e o f such s t i m u l a t i o n given d u r i n g a p o s t stress p e r i o d is a c o n s e q u e n c e o f s y m p a t h e t i c s t i m u l a t i o n . It is t h u s possible t h a t r e w a r d i n g s t i m u l a t i o n o f b r a i n areas t h a t p r o d u c e a p a r a s y m p a t h e t i c r e s p o n s e (e.g., s e p t u m ) w o u l d increase ulcer f o r m a t i o n if given d u r i n g t h e p o s t stress period. C o n s i s t e n t with this h y p o t h e s i s is t h e finding that blocking the peripheral parasympathetic system with s c o p o l a m i n e m e t h y l b r o m i d e i n h i b i t s ulcer f o r m a t i o n in rats s u b j e c t e d t o a similar stress p r o c e d u r e [ 19]. T h e m e c h a n i s m o f t h e p r o t e c t i v e effect o f b r a i n stimulat i o n o n u l c e r f o r m a t i o n is u n d e r i n v e s t i g a t i o n in o u r l a b o r a t o r y . We are c o n c e r n e d w i t h a n a s s e s s m e n t o f t h e possible c o n t r i b u t i o n o f a n u m b e r o f c o m p o n e n t s associa t e d w i t h effective b r a i n s t i m u l a t i o n : ( I ) r e w a r d i n g vs. n o n r e w a r d i n g ESB, (2) p a r a s y m p a t h e t i c vs. s y m p a t h e t i c ESB, a n d (3) b e h a v i o r a l l y a r o u s i n g vs. b e h a v i o r a l l y q u i e t i n g ESB.
*See text. fNumber in parentheses refers to number of lesions of a given size.
REFERENCES 1. Brady, J. V. Ulcers in the Executive Monkey. Scient. Am. 199: 9 5 - 1 0 0 , 1958. 2. Carmona, A. and J. Slangen. Effects of chemical stimulation of the hypothalamus upon gastric secretion. Physiol. Behav. 10: 6 5 7 - 6 6 1 , 1973. 3. Cox, V. C. and E. S. Valenstein. Attenuation of aversive properties of peripheral shock by hypothalamic stimulation. Science 149: 323-325, 1965. 4. Desiderato, O., J. R. Mackinnon and H. Hissom. Development of gastric ulceration in rats following stress termination. J. comp. physiol. PsychoL 87: 208-214, 1974. 5. Feldman, S., D. Birnbaum and A. Behar. Gastric secretion and acute gastroduodenal lesions following hypothalamie and preoptic stimulation. J. Neurosurg. 18: 6 6 1 - 6 7 0 , 1961. 6. Folkow, B. and E. H. Rubinstein. Behavioral and gastrointestinal changes (motility and blood flow) induced by electrical stimulation of the lateral hypothalamus in cats. Acta physiol, scand. 59: 44, 1963. 7. Freimark, S. J. Effects of electrical stimulation of the brain on the formation of acute gastric lesions. Physiol. Behav. 11: 855-859, 1973. 8. Hamilton, L. W. and F. A. Katske. Rapid gastric ulceration in modified two-way shuttlebox. Physiol. Psychol. 1: 188-190, 1973. 9. Lett, B. T. and C. W. Harley. Stimulation of lateral hypothalamus during sickness attenuates learned flavor aversions. Physiol. Behav. 12: 7 9 - 8 3 , 1974. 10. Long, D. M., A. S. Leonard, S. N. Chou and L. A. French. Hypothalamus and gastric ulceration. I. Gastric effects of hypothalamic lesions. II. Production of gastrointestinal ulceration by chronic hypothalamic stimulation. Archs Neurol. 7: 167-175; 176-183, 1962.
11. Mahl, G. F. Effects of chronic fear on gastric secretion of HC1 in dogs. Psychosom. Med. 11: 30, 1949. 12. Mayer, D. J., T. L. Wolfe, H. Akil, B. Carder and J. C. Liebeskind. Analgesia from electrical stimulation in the brain stem of the rat. Science 174: 1351-1354, 1971. 13. Mikhall, A. A. Effects of acute and chronic stress situations on stomach acidity in rats. J. comp. physiol. Psychol. 74: 2 3 - 2 7 , 1971. 14. Par6, W. P. and A. Livingston. Shock predictability and gastric secretion in the chronic fistula rat. Physiol. Behav. 11: 5 2 1 - 5 2 6 , 1973. 15. Pellegrino, L. J. and A. J. Cushman. A Stereotaxic Atlas of the Rat Brain. New York: Meredith Publishing Company, 1967. 16. Perez-Cruet, J. Heart rate: Differential effects of hypothalamic and septal self-stimulation. Science 140: 1235-1236, 1963. 17. Reis, D. J., D. J. Moorhead and M. Rifkin. Changes in adrenal e n z y m e s synthesizing catecholamines in attack behavior evoked by hypothalamic stimulation in the cat. Nature 229: 5 6 2 - 5 6 3 , 1971. 18. Rose, M. D. Pain reducing properties of rewarding electrical brain stimulation in the rat. J. comp. physiol. Psychol. 87: 6 0 7 - 6 1 7 , 1974. 19. Seiser, R. L. and V. P. Houser. Effects of Scopolamine Methylbromide on shock-induced gastric lesions in the unrestrained rat. Physiol. Behav. 13: 147-151, 1974. 20. Wald, E. R., J. R. Mackinnon and O. Desiderato. Production of gastric ulceration in the unrestrained rat. Physiol. Behav. 10: 825-827, 1973. 21. Weisz, J. D. The etiology of experimental gastric ulceration. Psychosom. Med. 19: 6 1 - 7 3 , 1957.
Reduction of Stomach Ulceration by Hypothalamic Stimulation in the Unrestrained Rat' JOHN MARSHALL 2 AND BRUCE MCCUTCHEON a
Psychology Department, State University o f New York at Albany, Albany N Y 12222 (Received 18 July 1975) MARSHALL, J. AND B. MCCUTCHEON. Reduction of stomach ulceration by hypothalamic stimulation in the unrestrained rat. PHYSIOL. BEHAV. 16(4) 391-393, 1976. - Gastric lesions were produced in unrestrained rats subjected to a 6 hr shock stress session followed by a 2 hr rest period. Electrical stimulation of the brain (posterior lateral hypothalamus) administered during the 2 hr post stress rest period significantly decreased ulcer development (i.e., percentage of animals showing lesions, number of lesions per animal, and severity of lesions) in the test group. ESB
Ulcers
Stress
Rat
ELECTRICAL stimulation of the hypothalamus has been shown to counteract a number of behavioral and physiological manifestations of aversive stimulation [3, 7, 9, 18]. Freimark [7], for example, showed that electrical stimulation of the posterior, lateral hypothalamus (a well-known rewarding stimulation area) reduced the severity of stomach ulceration caused by pain induced stress in rats. The design of his study called for rats to receive 1 to 5 randomly scheduled footshocks during a 50 min session in which they bar pressed for food. After 19 or 29 sessions, these animals developed significant stomach ulceration. They could be protected from this ulceration, however, by giving them I00, randomly scheduled 0.5 sec bursts of hypothalamic stimulation throughout each 50 min session. An important implication of this study is that the rewarding nature of the brain stimulation interfered with the development of the fear engendered by the unavoidable foot shock. The mechanism of this interference may result from a direct blocking of pain perception [ 12,18] or from blocking the formation of an aversive, stressful motivational state (fear) which would accompany anticipation of painful stimulation. Another quite different mechanism may account for the p r o t e c t i v e effect of hypothalamic stimulation. Such stimulation may have a direct effect on the physiological parameters of gastric activity which would counteract the irritative stress reaction in the stomach. Hypothalamic stimulation in both anesthetized and awake animals has been shown to produce marked changes in stomach acidity [2, 5, 10]. Although stomach acidity level has not proved to be a reliable correlate of acute ulceration [ 13,14], it is
possible that some other critical gastric physiological process is also affected by hypothalamic stimulation. Desiderato, et al. [4] employed an experimental design which can help separate the possible mechanism of fear reduction from the mechanism of direct antagonism of stomach ulceration. They found that pain stressed rats ulcerated much more severly if allowed to rest 2 hr in the safety of their home cage after a 6 hr random, unavoidable foot shock session than rats simply kept in the stress session for 8 hr. They suggested that the explanation for this result was that in the safe home cage there would be a strong parasympathetic rebound which would aggravate an ulceration process. Since lateral, posterior hypothalamic stimulation has been shown to produce sympathetic activation [6, 16, 17], we predicted that we could obtain a significant reduction in ulceration by providing the stressed rats with posterior hypothalamic stimulation while they rested 2 hr in a safe cage immediately following the stress induction session. This design thus allows us to examine the influence of hypothalamic stimulation on ulcer formation without altering pain or fear perception during the foot shock session itself. We report, in fact, that in many cases hypothalamic stimulation can completely protect the test rats from ulceration. METHOD
Animals Sixteen male6 Long Evans rats (Blue Spruce Farms), approximately 180 days old (300g), were individually housed in a temperature and humidity controlled room
1This research was supported in part by an Institutional Biomedial Research Grant to the Psychology Department. 2Predoctoral fellow, now at Albany Medical College, Albany, N.Y., 12208. 3Send reprint requests to second author. 391
392 with a normal 12 h r - 1 2 hr l i g h t - d a r k cycle. Approximately 3 weeks prior to testing, the animals were put on restricted diets which reduced their body weight to approximately 75% of their free feeding weight and maintained them within a 2 2 5 - 3 4 0 g range. All animals were food but not water deprived for a 48 hr period prior to the stress procedure. The experimental session ran from 800 hr to 1600 hr during the light period.
Apparatus The shock apparatus consisted of a 90 × 30 × 35 cm Plexiglas chamber which rested on an elevated grid f l o o r made of stainless steel rods 2 cm apart. Programmed electrical shock was automatically delivered through the grid from a Foringer Shock Power Supply unit (model 1154MII) and Foringer Grid Shock Scrambler (model 1925). Electrical stimulation of the brain (ESB) and rest treatments were administered in another room while animals were in a 50 x 40 × 50 cm Plexiglass chamber with solid floor. Brain stimulation was delivered by a 60 Hz AC stimulator. The duration was 0.5 sec and the rate was between 25 and 35 stimulations per min. All animals were unilaterally implanted with 0.5 mm dia. bipolar electrodes (Plastics Products Company, MS 303-.018-.312-SS.008). Surgery was performed under pentobarbitol anesthesia (60 mg/kg). All electrodes were aimed at the posterior aspect of the lateral hypothalamus. The DeGroot coordinates were: 1.5 mm lateral to midline, 1.6 mm posterior to bregma and 8.5 mm ventral from the surface of the cortex [ 15]. After 2 weeks of postsurgical recovery, the rats were tested for rewarding effects of electrical brain stimulation. At least 3 separate 1 hr tests were employed to make this assessment. An optimal current level as well as an average rate of bar pressing were determined for each animal. Only those animals that maintained an average rate of at least 350/15 min for hypothalamic sites were used in the test groups. Control group animals were those rats that did not show sufficient bar pressing behavior during the 3 test sessions (less than 25/15 min). The stress procedure, which was similar to that used by Hamilton and Katske [81 as well as Wald, MacKinnon and Desiderato [20], was carried out in the following manner: 2 food deprived rats, 1 experimental and 1 control, were each placed in a shock chamber and for the first 2 0 - 3 0 rain given only fixed interval shock alternating from one side of the grid floor to other side every 40 sec. Shock duration was 2 sec and shock intensity was 0.4 mA. After this initial period during which both animals learned to consistantly escape the shock by running to the opposite nonshock side of the grid floor, a discrete 2 sec duration shock was introduced to the safe side of the grid on a 50 sec variable interval schedule. At this point the current intensity was raised to 0.8 mA. The most common behavior of the rats to the unpredictable shock on the safe side of the grid was to run to the opposite shocked side of the chamber, and then to run back to the safe side and wait for the possible reoccurrence of the variable interval shock. After this 6 hr stress treatment, the experimental and control animals were removed from the shock apparatus and each placed in a plastic chamber, located in another room, where the experimental rat received 2 hr of automatic ESB and the control rat rested (no ESB) for 2 hr. Current intensity and delivery rate of ESB stimulation were the same as used to obtain the optimal rate of self-stimulation. On the average, the experi-
MARSHALL AND MCCUTCHEON mental rats received about 25, 0.5 sec bursts of stimulation per min at about 35 ~amps. No food or water was available during this period. Immediately following this 2 hr period, all animals were deeply anesthetized with 60 mg pentobarbitol for stomach removal and brain perfusion with 0,15 M NaC1 and 10% Formalin. The brains were removed and kept in 10% Formalin for 1 week. They were then cut into 40 ~ frozen section, stained with cresyl violet and examined for electrode placement. The stomachs were opened by an incision from the pylorus to the esophagus along the greater curvature and turned out for examination. The extent of the pathology, which was almost invariably restricted to the glandular portion of the stomach, was determined by quantifying the size and number of bloodfilled lesions using a 15 × binocular dissecting microscope and millimeter ruler. RESULTS The evaluation of gastric pathology consisted of: (1) the percentage of animals per group that exhibited ulcers, (2) the number of ulcers seen in each animal, and (3) ulcer severity as determined by weighted score based on the measured length of lesions in mm. The score given each ulcer was determined by applying an ulcer index to lesions of varying size. Lesions under I mm received a value of 1, those between 1 and 2.9 mm a value of 2, those between 3 and 4.9 mm a value of 3, and those over 5 mm a value of 4 [4]. The contents of Table 1 show the ulceration present in each animal in both groups. A significant difference was found between the mean number of ulcers in the 2 groups (t = 4.0, d.f. 14, p<0.01). Ulcer severity, as recorded by the ulcer score, was also found to be significantly higher in control group rats than in experimental rats, (t = 4.5, d.f. 14, p<0.01). Table 1 shows the comparison of ulceration indices between animals receiving ESB during the 2 hr post stress period and those allowed to rest during this period. Five rats in the experimental group showed no evidence of ulceration and little, if any, stomach irritation. Electrode placements were histologically determined for 7 out of 8 self-stimulating rats. Six animals had electrodes in the region of the MFB in the posterior lateral hypothalamus and I animal had the electrode in a more posterior location near the substantia nigra.
DISCUSSION Hypothalamic stimulation greatly reduces the incidence of gastric ulcers in active rats following relatively short stress treatment. The experimental procedure results in ulcer reduction without direct modification of the footshock stress period by the brain stimulation. Although most early attempts to explain the formation of stress induced gastric lesions were based on an increase in gastric acid secretion [ 11,21 ], more recent findings have not supported the hypersecretion hypothesis [1, 13, 14]. Perhaps a more helpful way of explaining the mechanism behind ulcer formation following stress would be in terms of the relative activity of the sympathetic and parasympathetic autonomic system responses and the known vascular and hormonal changes associated with them [ 6,17]. Situations that would tend to increase parasympathetic responses following high sympathetic activity, such as the immediate return to a safe
393
R E D U C T I O N O F U L C E R A T I O N BY S T I M U L A T I O N TABLE 1 ULCER FORMATION IN EXPERIMENTAL AND CONTROL GROUPS
Group Stress and ESB
Rat No. 1 2 3 4 5 6 7 8
0 2 0 2 0 0 2 0 0.75
9 I0 11 12 13 14
3 6 5 3 2 10
Mean Values Stress and Rest
15 16 Mean Values
No. of Ulcers
7 3 4.8
Size of Ulcer (mm) 0 1, 1 0 <1, <1 0 0 1.5, <1 0 0.83 (2)1, 2"t (6)1 (4)1, 2 (3)1 4, 1 (5)1.5, (3)1 (2)2 (4)1, (3)2 2, (2)1 1.3
Ulcer Body Weight Score* (g) 0 4 0 2 0 0 3 0 1.1
240 280 300 300 240 335 270 285 281
6 12 10 6 5 20
225 300 220 240 270 340
14 6 9.8
315 225 266
e n v i r o n m e n t f o l l o w i n g s h o r t - t e r m s h o c k stress, m a y b e p a r t i c u l a r l y effective in p r o d u c i n g r a p i d a n d severe ulceration. Conversely, t h e m a i n t e n a n c e o f high s y m p a t h e t i c a c t i v i t y f o l l o w i n g stress t e r m i n a t i o n m a y h a v e a n o p p o s i t e effect. Since s t i m u l a t i o n o f t h e lateral h y p o t h a l a m u s h a s b e e n k n o w n t o p r o d u c e s y m p a t h e t i c - l i k e r e s p o n s e s in t h e g a s t r o i n t e s t i n a l t r a c t [ 6 ] , in the c a r d i o v a s c u l a r s y s t e m [ 1 6 ] , a n d in t h e a d r e n a l s y s t e m [ 1 7 ] , it m a y b e t h a t t h e p r o t e c t i v e n a t u r e o f such s t i m u l a t i o n given d u r i n g a p o s t stress p e r i o d is a c o n s e q u e n c e o f s y m p a t h e t i c s t i m u l a t i o n . It is t h u s possible t h a t r e w a r d i n g s t i m u l a t i o n o f b r a i n areas t h a t p r o d u c e a p a r a s y m p a t h e t i c r e s p o n s e (e.g., s e p t u m ) w o u l d increase ulcer f o r m a t i o n if given d u r i n g t h e p o s t stress period. C o n s i s t e n t with this h y p o t h e s i s is t h e finding that blocking the peripheral parasympathetic system with s c o p o l a m i n e m e t h y l b r o m i d e i n h i b i t s ulcer f o r m a t i o n in rats s u b j e c t e d t o a similar stress p r o c e d u r e [ 19]. T h e m e c h a n i s m o f t h e p r o t e c t i v e effect o f b r a i n stimulat i o n o n u l c e r f o r m a t i o n is u n d e r i n v e s t i g a t i o n in o u r l a b o r a t o r y . We are c o n c e r n e d w i t h a n a s s e s s m e n t o f t h e possible c o n t r i b u t i o n o f a n u m b e r o f c o m p o n e n t s associa t e d w i t h effective b r a i n s t i m u l a t i o n : ( I ) r e w a r d i n g vs. n o n r e w a r d i n g ESB, (2) p a r a s y m p a t h e t i c vs. s y m p a t h e t i c ESB, a n d (3) b e h a v i o r a l l y a r o u s i n g vs. b e h a v i o r a l l y q u i e t i n g ESB.
*See text. fNumber in parentheses refers to number of lesions of a given size.
REFERENCES 1. Brady, J. V. Ulcers in the Executive Monkey. Scient. Am. 199: 9 5 - 1 0 0 , 1958. 2. Carmona, A. and J. Slangen. Effects of chemical stimulation of the hypothalamus upon gastric secretion. Physiol. Behav. 10: 6 5 7 - 6 6 1 , 1973. 3. Cox, V. C. and E. S. Valenstein. Attenuation of aversive properties of peripheral shock by hypothalamic stimulation. Science 149: 323-325, 1965. 4. Desiderato, O., J. R. Mackinnon and H. Hissom. Development of gastric ulceration in rats following stress termination. J. comp. physiol. PsychoL 87: 208-214, 1974. 5. Feldman, S., D. Birnbaum and A. Behar. Gastric secretion and acute gastroduodenal lesions following hypothalamie and preoptic stimulation. J. Neurosurg. 18: 6 6 1 - 6 7 0 , 1961. 6. Folkow, B. and E. H. Rubinstein. Behavioral and gastrointestinal changes (motility and blood flow) induced by electrical stimulation of the lateral hypothalamus in cats. Acta physiol, scand. 59: 44, 1963. 7. Freimark, S. J. Effects of electrical stimulation of the brain on the formation of acute gastric lesions. Physiol. Behav. 11: 855-859, 1973. 8. Hamilton, L. W. and F. A. Katske. Rapid gastric ulceration in modified two-way shuttlebox. Physiol. Psychol. 1: 188-190, 1973. 9. Lett, B. T. and C. W. Harley. Stimulation of lateral hypothalamus during sickness attenuates learned flavor aversions. Physiol. Behav. 12: 7 9 - 8 3 , 1974. 10. Long, D. M., A. S. Leonard, S. N. Chou and L. A. French. Hypothalamus and gastric ulceration. I. Gastric effects of hypothalamic lesions. II. Production of gastrointestinal ulceration by chronic hypothalamic stimulation. Archs Neurol. 7: 167-175; 176-183, 1962.
11. Mahl, G. F. Effects of chronic fear on gastric secretion of HC1 in dogs. Psychosom. Med. 11: 30, 1949. 12. Mayer, D. J., T. L. Wolfe, H. Akil, B. Carder and J. C. Liebeskind. Analgesia from electrical stimulation in the brain stem of the rat. Science 174: 1351-1354, 1971. 13. Mikhall, A. A. Effects of acute and chronic stress situations on stomach acidity in rats. J. comp. physiol. Psychol. 74: 2 3 - 2 7 , 1971. 14. Par6, W. P. and A. Livingston. Shock predictability and gastric secretion in the chronic fistula rat. Physiol. Behav. 11: 5 2 1 - 5 2 6 , 1973. 15. Pellegrino, L. J. and A. J. Cushman. A Stereotaxic Atlas of the Rat Brain. New York: Meredith Publishing Company, 1967. 16. Perez-Cruet, J. Heart rate: Differential effects of hypothalamic and septal self-stimulation. Science 140: 1235-1236, 1963. 17. Reis, D. J., D. J. Moorhead and M. Rifkin. Changes in adrenal e n z y m e s synthesizing catecholamines in attack behavior evoked by hypothalamic stimulation in the cat. Nature 229: 5 6 2 - 5 6 3 , 1971. 18. Rose, M. D. Pain reducing properties of rewarding electrical brain stimulation in the rat. J. comp. physiol. Psychol. 87: 6 0 7 - 6 1 7 , 1974. 19. Seiser, R. L. and V. P. Houser. Effects of Scopolamine Methylbromide on shock-induced gastric lesions in the unrestrained rat. Physiol. Behav. 13: 147-151, 1974. 20. Wald, E. R., J. R. Mackinnon and O. Desiderato. Production of gastric ulceration in the unrestrained rat. Physiol. Behav. 10: 825-827, 1973. 21. Weisz, J. D. The etiology of experimental gastric ulceration. Psychosom. Med. 19: 6 1 - 7 3 , 1957.