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1 Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine and Food Intake Laboratory, University of California, Davis, California 95616; and 2 Baylor College of Dentistry, Texas A&M University System Health Sciences Center, Department of Biological Sciences, Dallas, Texas 75246
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Both total subdiaphragmatic vagotomy (TVAGX) and serotonin3 receptor blockade with tropisetron or ondansetron attenuate amino acid-imbalanced diet (Imb) anorexia. Total vagotomy is less effective than tropisetron in reducing Imb-induced anorexia and also blunts the tropisetron effect. With the use of electrocautery at the subdiaphragmatic level of the vagus, we severed the ventral and dorsal trunks as well as the hepatic, ventral gastric, dorsal gastric, celiac, and accessory celiac branches separately or in combination to determine which vagal branches or associated structures may be involved in these responses. Rats were prefed a low-protein diet. On the first experimental day, tropisetron or saline was given intraperitoneally 1 h before presentation of Imb. Cuts including the ventral branch, i.e., TVAGX, ventral vagotomy (above the hepatic branch), and hepatic + gastric vagotomies (but not hepatic branch cuts alone) caused the highest (P < 0.05) Imb intake on day 1 with or without tropisetron. The responses to tropisetron were not affected significantly. On days 2-8, groups having vagotomies that included the hepatic branch recovered faster than sham-treated animals. Because the hepatic and gastric branches together account for most of the vagal innervation to the proximal duodenum, this area may be important in the initial responses, whereas structures served by the hepatic branch alone apparently act in the later adaptation to Imb.
amino acid; diet; amino acid-imbalanced diet; amino acid deficiency; rat; food intake; body weight; vagus; serotonin
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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INGESTION OF AN AMINO acid-imbalanced diet (Imb) triggers a rapid feeding depression in rats (reviewed in Refs. 14, 18, 31). In the presence of a serotonin (5-HT) agonist, the anorectic response to Imb is exacerbated (15). Blockade of the 5-HT3 receptor with tropisetron or ondansetron attenuates this anorectic response (17, 22) on the first experimental day (day 1). Intraperitoneal injections of quaternized tropisetron, which does not cross the blood-brain barrier, have an effect similar to the nonquaternized form (20), suggesting a peripheral site for this effect of tropisetron. Moreover, total subdiaphragmatic vagotomy (TVAGX) attenuates the feeding depression associated with Imb diets, although not as well as tropisetron (37), showing involvement of the vagus. A peripheral site of action for tropisetron in this model is also supported by the observation that tropisetron and TVAGX are not additive in ameliorating Imb anorexia.
Peripheral injections of 5-HT cause a greater reduction of food intake in TVAGX than in sham-operated rats (13), indicating that vagal components can modify the peripheral effect of 5-HT in food-intake suppression. In support of this finding, an intact vagal system is required to observe the maximal effect of tropisetron on Imb intake (37). It is not yet known which branches of the vagus participate in the anorectic/aversive responses to Imb or the role of 5-HT therein.
The vagus innervates major portions of the gastrointestinal system and is important in the control of feeding. In the rat, at the level of the diaphragm, the vagus is composed of a ventral and a dorsal trunk. Below the diaphragm, the ventral trunk separates into the hepatic, accessory celiac, and ventral gastric branches, whereas the dorsal trunk separates into the celiac and dorsal gastric branches (21, 28). Gastrointestinal innervation patterns have shown that the gastric branches serve the stomach and proximal duodenum, the hepatic branch serves the proximal duodenum, and the celiac and accessory celiac branches serve more distal portions of the intestine (5).
Preliminary findings in our laboratories suggest that the ventral and dorsal trunks may play very different roles in the anorectic responses to Imb. As noted above, the ventral trunk contains the hepatic branch, and although cutting the hepatic branch does not affect Imb intake on day 1, there may be a role for the hepatic branch in mediating the adaptive phase of the responses to Imb that occurs over the next few days (2, 4). Total liver denervation, including fibers that pass through the liver, does not affect the initial attenuation of feeding with Imb nor does it impair the effectiveness of tropisetron (2). However, more recent evidence suggests that cutting the hepatic branch alone can accelerate the adaptive phase of the responses to Imb over several days (4). Also, after a few days on a lysine-deficient diet, responses to infusion of the limiting amino acid lysine into the hepatic portal vein cause a 100-fold increase in the firing rate of hepatic branch neurons (36). Thus the role of the hepatic branch in the anorectic responses to and recovery from the amino acid deficiency induced by eating Imb is complicated and not fully elucidated. Adding to the complexity of the problem, Berthoud and Neuhuber (6) have suggested that although the hepatic branch goes to and through the liver, it may not innervate liver parenchyma, but instead it may innervate other structures such as the bile ducts, pancreas, and duodenum. The role, if any, of the other subdiaphragmatic branches of the vagus in the rat's response to Imb diets is unknown. Therefore, in the present studies, we used selective partial vagotomies to evaluate the roles of the several vagal branches in Imb intake and in the responses to 5-HT3 blockade with tropisetron in the initial and adaptive phases of the aminoprivic model.
The major findings of these studies are 1) confirmation that a hepatic branch cut alone can accelerate adaptation to Imb over several days, i.e., phase 3 (14) of the feeding responses and 2) innervation of the proximal duodenum and/or distal stomach by the hepatic branch together with at least one of the gastric branches (5) appears to be important in the early learning phase (phase 2) of the anorectic response on the first day of exposure to Imb, which occurs after recognition of the deficiency (phase 1). From the responses measured, neither initial recognition of the deficiency nor the responses to tropisetron appeared to be affected by the treatments used in these experiments.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
Male Sprague-Dawley rats were purchased from Harlan Sprague Dawley (Houston, TX) or from Simonsen Laboratories (Gilroy, CA). All animal protocols were approved by the appropriate institutional Animal Use and Care Committee and followed National Institutes of Health Guidelines. Rats were housed individually in stainless steel cages in the vivarium at 22°C on a 12:12-h light-dark cycle. In addition to room lighting, two 25-W red lightbulbs were kept on at all times to facilitate food intake measurements during the dark phase. To allow adaptation to the vivarium, the rats were fed a stock diet (Purina Rat Chow no. 5012, Ralston, St. Louis, MO) for 1 wk. Water was freely available throughout the study. After adaptation to the vivarium, the rats were fasted for 24 h and then subjected to various combinations of partial subdiaphragmatic vagotomies. Before surgery, the rats were anesthetized, as previously described, with either ketamine and xylazine (3) or with a mixture of ketamine, xylazine, and acepromazine, plus subcutaneous atropine to prevent respiratory distress (37). After surgery, the incisions were closed with the use of sutures and wound clips. All animals received an intramuscular injection of 10 mg/kg of penicillin G procaine (10 mg/ml, VEDCO, St. Joseph, MO) and were kept warm under a heat lamp during recovery from anesthesia.Dietary Treatments
After surgery, the rats were fed a milk-based liquid diet (Carnation sweetened condensed milk, Nestle, Glendale, CA) that was diluted with deionized water, 2:1 vol/vol, for 3 days. After the liquid diet, animals in experiment 1 and experiment 2, trials 1b, 1c, and 2c received a 17% casein-based gel diet (all of the diets are described in detail in Refs. 17, 37). This was given fresh every day for 5 or 6 days. In experiment 2, trials 1a, 2a, and 2b, the animals were given an isoleucine-corrected diet in gel form, also for 5 or 6 days. These liquid and gel diets were used to allow recovery of gastrointestinal function after the various vagotomies.Next, the rats were switched to a dry powdered low-protein basal diet for a 10-day prefeeding period (17, 37). The basal diet contained purified L-amino acids as the protein source with isoleucine as the growth-limiting amino acid. The Imb was the same as the basal diet, with the addition of a mixture of all of the indispensable amino acids except for isoleucine, which was the growth-limiting amino acid. The corrected diet was the same as Imb, but it was corrected with an additional 1.0% of isoleucine to bring the amino acid profile into physiological balance. When amino acids were added, the carbohydrate fraction was adjusted proportionately. To aid gastrointestinal clearance in the vagotomized animals, fiber was not included in any of the defined diets.
Food-Intake Measurements
Starting at lights out (0 h) for the last 3 days on basal diet, cumulative intake, corrected for spillage, was measured at 3, 6, 9, 12, and 24 h. These data served as basal-baseline control values for each rat. After this, the rats were presented with Imb, and intakes for day 1 were recorded at the times listed above; cumulative intake for the first 24 h served as day 1 intake for comparison with later daily food intake measures. Daily Imb intakes, corrected for spillage, were recorded for the next several experimental days (from day 2 to day 7 or 8) depending on the experimental protocol. When used, the corrected diet was offered after the completion of Imb feeding, and intake of the corrected diet was also measured daily.Experiment 1: Subdiaphragmatic Truncal Vagotomies
This experiment followed a 4 × 2 design with four subdiaphragmatic surgical conditions and two drug conditions. The surgeries performed were 1) sham, 2) a TVAGX above the hepatic branch on the ventral trunk and above the celiac branch on the dorsal trunk (cuts 1 and 2 in Fig. 1) following the method of Ritter and Taylor (30), 3) a unilateral ventral cut above the hepatic branch (cut 1 in Fig. 1), or 4) a unilateral dorsal cut above the celiac branch (cut 2 in Fig. 1). When the proper branch was visualized and isolated, it was severed by electrocautery. Both the ventral trunk and the hepatic branch were isolated and cauterized independently for the ventral trunk cut group. In the sham operation, the experimental surgery was replicated with all branches of the vagus left intact and only touched with the tip of a cotton swab, moistened with saline. Body weights of the groups at the time of surgery were similar (P > 0.10, nonsignificant): sham-saline 260 ± 5.4 g, TVAGX-saline 243.6 ± 4.3 g, ventral cut-saline 252.3 ± 5.0 g, dorsal cut-saline 249.5 ± 7.8 g, sham-tropisetron 248.9 ± 5.5 g, TVAGX-tropisetron 245.7 ± 5.6 g, ventral cut-tropisetron 259.3 ± 6.4 g, and dorsal cut-tropisetron 254.5 ± 4.5 g.
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After surgery, the animals were fed as described in Dietary Treatments. Food intake was recorded at the intervals described above during the last 3 basal-baseline days. Body weights after the last basal-diet day were again similar (P < 0.38, nonsignificant): sham-saline 315.6 ± 4.3 g, TVAGX-saline 299.6 ± 5.4 g, ventral trunk cut-saline 305.6 ± 6.0 g, dorsal trunk cut-saline 309.6 ± 5.8 g, sham-tropisetron 315.7 ± 4.3 g, TVAGX-tropisetron 305.2 ± 5.9 g, ventral trunk cut-tropisetron 309.6 ± 6.3 g, dorsal trunk cut-tropisetron 313.6 ± 5.1 g. On the day the Imb was to be introduced, 1 h before lights out, the basal-diet food cups were removed and each rat received an intraperitoneal injection. The two drug conditions were 1) saline (0.9% NaCl) given in a volume of 1 ml/kg body wt, and 2) tropisetron (endo- 8-Methyl-8-azabicyclo[3.2.1]oct-3-ol Indole-3-yl-carboxylate hydrochloride, Research Biochemicals, Natick, MA) given in a dose of 9 mg/kg ip, as determined in previous dose-response studies (17, 22). Tropisetron was administered to one-half of each surgical group, and saline was given to the other half of the animals. At lights out (0 h), all rats received a food cup containing Imb, and then interval (day 1) and daily consumption (days 2-7) were measured. On day 8, the diet was changed to the corrected diet, and daily food-intake measurements were continued through day 12. After verification of surgeries, the group sizes were: sham-saline n = 7, sham-tropisetron n = 6, TVAGX-saline n = 6, TVAGX-tropisetron n = 6, ventral cut-saline n = 6, ventral cut-tropisetron n = 6, dorsal cut-saline n = 6, and dorsal cut-tropisetron n = 6.
Experiment 2: Selective Partial Vagotomies
Trial 1: ventral branch vagotomies including the hepatic branch. trial 1a. The surgeries performed were 1) sham, 2) hepatic branch cut (illustrated as cut 3 in Fig. 1), 3) hepatic branch cut plus accessory celiac cut (cuts 3 + 4 in Fig. 1), 4) hepatic branch cut + ventral gastric branch cut below the accessory celiac branch (hepatic + ventral gastric cuts: cuts 3 + 5 in Fig. 1), 5) TVAGX, 6) ventral cut, or 7) unilateral ventral cut below the hepatic branch (ventral-B cut), including the accessory celiac and ventral gastric branches (cuts 4 + 5 in Fig. 1). The ventral-B cut was included to test all possible combinations of ventral branches. The body weights of the groups were similar (P > 0.10, not significant) at the time of surgery: sham 265.1 ± 3.08 g, hepatic branch cut 272.9 ± 3.63 g, hepatic + accessory celiac branches cut 270.0 ± 3.55 g, hepatic + ventral gastric branches cut 263.4 ± 3.82 g, TVAGX 268.7 ± 3.33 g, ventral cut 266.5 ± 3.71 g, and ventral-B cut 263.1 ± 2.86 g. After surgery, the animals were fed as described under Dietary Treatments.
On the last basal-diet day, the average group weights differed, P < 0.01 (sham 284.9 ± 4.4 g, hepatic branch cut 290.4 ± 5.1 g, hepatic + accessory celiac cut 290.3 ± 4.1 g, hepatic + ventral gastric branch cuts 283.6 ± 5.9 g, TVAGX 263.0 ± 5.2 g, ventral trunk cut 285.4 ± 4.4 g, and ventral-B cut 282.9 ± 5.1 g). The difference was due to the TVAGX group, which weighed less than the sham group (P < 0.01). After verification of nerve transection, the following group sizes remained: sham n = 7, hepatic branch cut n = 8, hepatic + accessory celiac branch cuts n = 16, hepatic + ventral gastric branch cuts n = 14, TVAGX n = 11, ventral cut n = 11, and ventral-B cut n = 10. TRIAL 1B. The surgeries were 1) sham, 2) TVAGX, and 3) hepatic + ventral gastric branch + dorsal trunk cuts. The dorsal trunk was also cut in this experiment, because we wanted to verify that the dorsal trunk cut would not alter the effects seen with cuts of the hepatic and ventral gastric branches. Cuts of the dorsal branch in experiment 1 had indicated that this trunk by itself, containing the celiac and dorsal gastric branches, has no effect on the intake of Imb. Body weights at the time of surgery were 1) sham 286.0 ± 3.1 g, 2) TVAGX 279.9 ± 2.7 g, and 3) hepatic + ventral gastric branch + dorsal trunk cuts 282.9 ± 4.0 g (P > 0.10, nonsignificant). There were no significant differences for food intake at any interval among the groups during the basal-diet prefeeding period (P > 0.10, not significant). Body weights did differ among the groups at the end of the prefeeding period due to the sham group's weight being significantly higher than the other two groups: sham 340.3 ± 3.0 g, TVAGX 313.8 ± 5.2 g, and hepatic + ventral gastric branch + dorsal trunk cut 310.1 ± 4.0 g, P = 0.0003. After verification of the surgeries, the group sizes were: sham n = 6, TVAGX n = 8, and hepatic + ventral gastric branch + dorsal trunk cuts n = 9. TRIAL 1C. The surgeries were 1) sham, 2) TVAGX, and 3) hepatic + dorsal gastric branch (cuts 3 + 7 in Fig. 1). The dorsal gastric branch was cut in this experiment, because we wanted to learn whether the dorsal gastric branch cut would have effects similar to those seen in trial 1b with the ventral gastric branch when combined with the hepatic branch cut. Body weights at the time of surgery were 1) sham 228.9 ± 11.8 g, 2) TVAGX 220.6 ± 13.0 g, and 3) hepatic + dorsal gastric branch cuts 236.0 ± 11.8 g (P > 0.10, nonsignificant). There were no significant differences for food intake at any interval among the groups during the basal-diet prefeeding period (P > 0.10, not significant). Body weights also did not differ among the groups at the end of the prefeeding period: sham 331.6 ± 9.8 g, TVAGX 319.6 ± 6.1 g, and hepatic + dorsal branch cut 331.1 ± 5.8 g, P > 0.10, not significant. After verification of the surgeries, the group sizes were: sham n = 5, TVAGX n = 4, and hepatic + dorsal branch cuts n = 4.Trial 2: selective ventral vagotomies sparing the hepatic branch. Trials 2a and 2b were conducted at different times, but they were identical except that in trial 2a the rats were given surgical treatments and saline injections only. In trial 2b, they were given the same surgeries, but they were injected with tropisetron rather than saline. Body weights were measured daily during both of these trials. Trial 2c was done to clarify observations made in previous trials.
TRIAL 2A. The surgeries performed were 1) sham, 2) ventral gastric branch cut (cut 1 in Fig. 1), 3) dorsal gastric branch cut below the celiac branch (cut 7 in Fig. 1), 4) celiac + accessory celiac cuts (cuts 4 and 6 in Fig. 1), and 5) ventral-B + dorsal trunk cuts [bilateral vagotomy below the hepatic branch (BILAT-B) cuts 2, 4, and 5]. The body weights of these groups were similar on the day of surgery 1) sham 223.6 ± 2.5 g, 2) ventral gastric branch cut 232.9 ± 3.4 g, 3) dorsal gastric branch cut 224.9 ± 1.8 g, 4) celiac + accessory celiac cut 231.3 ± 4.7 g, and 5) ventral-B + dorsal trunk cut 231.4 ± 2.2 g, P > 0.10, nonsignificant. Cumulative consumption of the basal diet by the groups differed at 3 h, P < 0.01, due to the ventral gastric (6.1 ± 0.3 g) and celiac + accessory celiac branch cuts (6.1 ± 0.5 g) groups that consumed more (P < 0.05) basal diet than did the sham group (5.1 ± 0.3 g). Basal-diet intakes of the dorsal gastric branch cut (5.4 ± 0.2 g) and BILAT-B cut (5.0 ± 0.2 g) groups did not differ from the sham group. Cumulative basal-diet intakes for 0-6, 0-9, 0-12, and 0-24 h did not differ among the groups (data not shown). On the last basal-diet day, the body weights of the groups differed, P < 0.001, due to the BILAT-B cut group, which weighed less than the other groups (P < 0.05): sham 279.6 ± 5.7 g, ventral gastric branch cut 267.8 ± 2.7 g, dorsal gastric branch cut 270.8 ± 3.6 g, celiac + accessory celiac cuts 269.8 ± 5.3 g, and BILAT-B cut 255.9 ± 9.8 g. After verification of the surgeries, the following group sizes remained 1) sham n = 10, 2) ventral gastric branch cut n = 13, 3) dorsal gastric cut n = 18, 4) celiac + accessory celiac cut n = 10, and 5) BILAT-B cut n = 17. Trial 2b was a repeat of trial 2a, except that the rats were injected with tropisetron as described in experiment 1. The body weights were similar among the groups (P > 0.10, nonsignificant) on the day of surgery 1) sham 211.8 ± 2.4 g, 2) ventral gastric branch cut 213.0 ± 4.2 g, 3) dorsal gastric cut 204.0 ± 3.0 g, 4) celiac + accessory celiac cut 211.6 ± 4.7 g, and 5) BILAT-B cut 213.0 ± 3.2 g. Cumulative consumption of basal diet by the groups was similar at all time points, with the exception of the 12-h measurement when the BILAT-B cut-tropisetron group consumed less than the sham-tropisetron group. This also occurred in trial 2a in the saline-treated groups having those two surgeries. On the last basal-diet day, before the rats were presented with Imb, the body weights of the groups differed, P < 0.05. Weights were: sham 237.6 ± 4.0 g, ventral gastric branch cut-tropisetron 235 ± 5.3 g, dorsal gastric branch cut-tropisetron 227.7 ± 3.9 g, celiac + accessory celiac branches cut-tropisetron 236.3 ± 5.3 g, and BILAT-B cut-tropisetron 218.9 ± 2.2 g. Again, the BILAT-B cut group weighed the least as in trial 2a. After verification of surgeries, the groups were 1) sham n = 12, 2) ventral gastric branch cut n = 10, 3) dorsal gastric branch cut n = 10, 4) celiac + accessory celiac cut n = 11, and 5) BILAT-B cut n = 11. Trial 2c was done because it was of interest to repeat two previous lesions. First, the BILAT-B cut-saline group had appeared to differ from the others in trials 2a and 2b; and second, the full dorsal trunk cut had no effect in our model, particularly in view of the results of experiment 2, trial 1c, in which the dorsal gastric branch appeared to be important when combined with the hepatic branch cut. The groups were 1) sham-saline, 2) sham-tropisetron, 3) BILAT-B cut-saline, 4) dorsal trunk cut-saline, or 5) dorsal trunk cut-tropisetron. Body weights at the time of surgery were again similar 1) BILAT-B cut-saline 233.4 ± 3.4 g, 2) dorsal trunk cut-saline 235.8 ± 2.7 g, 3) sham-saline 231.8 ± 3.9 g, 4) dorsal trunk cut-tropisetron 228.5 ± 2.6 g, and 5) sham-tropisetron 233.3 ± 3.2 g, P > 0.10, not significant. On the last day of basal-diet feeding, the groups' body weights differed, P < 0.006: sham-saline 313 ± 9.2 g, sham-tropisetron 307 ± 7.6 g, BILAT-B cut-saline 288 ± 4.6 g, dorsal trunk cut-saline 313 ± 5.3 g, and dorsal trunk cut-tropisetron 314 ± 3.2 g. Post hoc analysis showed that the differences were due to the BILAT-B cut group, which weighed less (P < 0.01) than the other groups as we had seen in trials 2a and 2b. Imb was introduced and both cumulative interval (day 1) and daily 24-h (days 2-8) intakes were recorded after saline or tropisetron injection. After verification of the lesions, the remaining group sizes were 1) sham-saline n = 6, 2) sham-tropisetron n = 6, 3) BILAT-B cut-saline n = 10, 4) dorsal trunk cut-saline n = 8, and 5) dorsal trunk cut-tropisetron n = 8.Verification of Vagotomies
Completeness of bilateral surgeries was verified at the end of each experiment by measuring the degree of stomach fill after 12-h access to rat chow; residual material in the stomach can be 10-fold greater in TVAGX rats than in sham-operated rats (37). Animals in the TVAGX group that had stomach contents weighing less than the greatest value from the sham group were discarded from the data set. Verification of the ventral trunk, dorsal trunk, accessory celiac, and celiac branch vagotomies was accomplished with the use of a Fluorogold retrograde tracer (Fluorochrome, Englewood, CO) as described by Powley et al. (27). The tracer was injected bilaterally and intraperitoneally at a dose of 0.5 mg per side per rat. After 3 days, the rats were anesthetized with pentobarbital sodium (42 mg/kg) and perfused with PBS followed by 10% Formalin-PBS. The brains were placed in 10% Formalin-PBS for 24 h and then transferred to a 10% sucrose-PBS solution for 2-7 days. The brain stems were frozen and later sectioned for histological review. Heavy bilateral fluorescent staining in the cells of the dorsal motor nucleus of the vagus indicated incomplete ventral or dorsal vagotomies, and these animals were discarded from the data set. Verification of vagotomies where gastric innervation was involved (appropriate groups in experiment 2, trials 1a, 1c, 2a, and 2b) was by observation of a lack of gastric motility changes after electrical stimulation of the transected branch above the cut, as used previously (3). Hepatic branch vagotomies were verified by observation of the absence of nerve fibers extending from the ventral trunk between the diaphragm and the accessory celiac branch.Statistical Analysis
For all food-intake measurements, intake of Imb is presented as a percentage of each rat's basal diet-baseline intake (% basal intake) so that each rat served as its own control. After verification of nerve transections, data for each trial were subjected to one- or two-way ANOVA (for the effects of surgery or surgery and drug where appropriate) for each of the intervals on day 1. Data for the 24-h measurements on day 1 and subsequent days were analyzed by repeated-measures ANOVA. Post hoc tests (Fisher's protected least-significant means or Duncan's tests) were used to determine differences among group means. Significance was assumed at P < 0.05. Data were analyzed with the use of SAS, 6.12 (SAS Institute, Cary, NC) or ABstat, release 6.51 (Anderson-Bell, Parker, CO) on the laboratory computers.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiment 1: Subdiaphragmatic Truncal Vagotomies
Effects of surgery and tropisetron
day 1.
The first day on Imb (day 1) the cumulative 24-h intakes of
the groups differed significantly (Fig.
2). As expected, all animals reduced
their Imb intake relative to their basal diet-baseline intake; values
for all eight groups ranged from 38.8 to 55.1% of their basal
diet-baseline intake. Also, as expected, tropisetron increased Imb
intake on day 1. During the first 3 h, there was a
significant drug effect (P < 0.04) with the usual
reduction of Imb intake attenuated in all tropisetron-treated groups.
By 6 h, the overall effect was still due to drug-treated groups, as the tropisetron effect for all of the groups remained significant (P < 0.001) at 6, 9, and 12 h. By 24 h, all
tropisetron-treated groups had similar Imb intakes (70-75% of
basal-diet baseline).
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in Fig. 2). However, there was a significant (P < 0.05) surgery × tropisetron interaction at
9, 12, and 24 h. Notably, at 9 h, both the TVAGX-saline and
ventral trunk cut-saline groups (
and 
,
respectively) were consuming more of Imb (significance of the surgery
effect, P < 0.02) than the dorsal trunk cut-saline and
sham-saline groups ( and 
in Fig. 2). These significant differences continued at the 12- and 24-h measurements. By 24 h,
the ventral trunk cut-saline and TVAGX-saline groups were also eating
more (61 and 58%, respectively, P = 0.002) Imb than
the sham-saline group that ate 41% of baseline, by the end of
day 1. Intake of Imb by the ventral trunk cut-saline and
TVAGX-saline groups was increased to a level that did not differ from
that of the tropisetron-treated groups, and it remained higher than the
saline-treated sham and dorsal trunk cut groups throughout day
1.
The adaptation phase of the responses to Imbdays 2-7.
There were significant differences among the surgical groups that
extended throughout all 7 days on Imb (P < 0.003, Fig.
3A) and persisted (albeit in
reversed order of increasing food intake) after the diet was changed to
the corrected diet for days 8-12 (P < 0.0001, Fig. 3B). On day 2 of Imb feeding, there
was a residual drug effect (P < 0.004) such that the
TVAGX-tropisetron and ventral trunk cut-tropisetron groups ate
significantly (P < 0.03) more than their respective
saline groups (Fig. 3A). There were no significant drug
effects after day 2. On days 3, 4, and
6, both ventral cut groups' and both TVAGX groups'
consumption of Imb was similar and significantly (P < 0.04) elevated over all of the saline groups, showing accelerated
adaptaion to Imb. On days 5 and 7 also, Imb intakes of the TVAGX-saline and ventral trunk cut-saline groups were
significantly greater than those of the sham-saline group, P < 0.05 (Fig. 3A). The tropisetron-treated
dorsal trunk cut and sham groups remained similarly low (Fig.
3A).
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Effects of surgery and tropisetron on corrected diet intakedays
8-12.
After the animals were switched to the corrected diet, all groups
increased their food intake as expected, with a moderate compensatory
hyperphagia; there were no differences among the groups on day
8 (Fig. 3B). However, for days 9-12,
there were significant surgical effects (P < 0.003) with
the groups reversed from the results with Imb on days
2-7 (compare Fig. 3, A and B; note
different ranges of values on the ordinates). Post hoc testing revealed
that on day 12, the sham-saline group was still eating the
most of the corrected diet (112.9% of basal-diet intake), and the
TVAGX-saline and ventral trunk cut-saline groups were eating the least
(87% of basal diet, P = 0.0001; and 94% of basal diet, P = 0.002, respectively). This reciprocal effect
may be due to the fact that these groups did not decrease their intake of Imb diet as severely, with the result that their need for a compensatory hyperphagia was not as great. There was a significant residual tropisetron effect in the TVAGX group on day 9 only
(P < 0.02), but there were no other drug effects on
the intake of corrected diet through day 12.
Experiment 2: Selective Subdiaphragmatic Vagotomies
Trial 1: ventral vagotomies including ablation of the hepatic branch. trial 1a. Over the 7-day measurement period on Imb, the TVAGX group had the greatest Imb intake, and the ventral-B cut group had the lowest Imb intake (data not shown). These differences were reflected in body weight differences.
The data for each rat's body weight on days 1-7 were transformed to a percentage of that rat's body weight on the last day of basal-diet feeding, and then daily comparisons among the groups were made. On days 1-3, the body weights of all the groups were similar. Group differences in body weights became apparent (P < 0.02) over the last 4 days that the rats were given Imb. During days 3-5, an increasing trend in body weight gain began to emerge among the groups that was reflective of their Imb consumption. As expected from experiment 1, by day 4 the TVAGX group weighed more (P < 0.01) than the sham group. The weight of the TVAGX group continued to diverge from the sham group over days 5-7. A trend was also apparent, starting on day 4, for the ventral trunk cut and the hepatic + ventral gastric branch cut groups to gain more weight than the sham group. This difference became significant for both of these groups on days 6 and 7. By day 6, the body weights of the TVAGX group were significantly (P < 0.01) increased over all groups except the ventral trunk cut group, in which the body weights did not differ from the hepatic + ventral gastric branch cut group. These results suggested that the ventral trunk effects in Imb anorexia required the hepatic and gastric branches, but not the accessory celiac branch, and that other combinations of cuts among the branches of the ventral trunk were ineffective. TRIAL 1B. When the Imb diet was fed on day 1, significant differences were seen after 3 h (P < 0.005, Fig. 4A). For the 6- through 24-h measurements, cumulative Imb intakes for the TVAGX group were greater (all P < 0.05) than those of the sham group. The group having the combined hepatic + ventral gastric branches + dorsal trunk cuts also consumed significantly more Imb diet than the sham group at 12 h (P < 0.02), with trends toward significance as early as 6 h (P < 0.07) and in the cumulative data for 24 h (P < 0.06). Notably, the Imb intake for the group having combined hepatic, ventral gastric, and dorsal cuts did not differ significantly from the TVAGX group at any time measured, and it was significantly elevated over the sham group (P < 0.05), although only at 12 h as noted (Fig. 4A). This is consistent with the observations for the hepatic + ventral gastric branch cut group in trial 1a and ventral trunk vagotomy seen in experiment 1.
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|
Trial 2: selective ventral vagotomies sparing the
hepatic branch.
Trials 2a and 2b were done separately, but the
data for day 1 from the two trials are presented together in
Fig. 6 to allow comparison with
experiment 1.
|
) whose 3-, 6-, 12-, and 24-h cumulative Imb
intakes were significantly less than the sham-saline () group's
intake. Over the next 7 experimental days, Imb intakes did not differ
(P > 0.10, not significant) among the surgical groups;
the expected adaptation to Imb (phase 3) was unaffected by
any of the surgeries as their Imb intakes increased similarly over
days 2-8 (data not shown). Consistent with the food
intake data, while on Imb, the saline-treated groups' daily body
weights, expressed as a percentage of their body weight at the time Imb
was introduced, also did not differ (P > 0.10, not
significant) over the 8-day measurement period.
TRIAL 2B: EFFECTS OF TROPISETRON.
Although statistical comparisons between the respective saline-
and tropisetron-treated groups were not done because the trials were
conducted separately, tropisetron clearly increased Imb intake in all
groups over the course of day 1 (filled symbols in Fig. 6).
Cumulative Imb intake on day 1 did not differ among the
tropisetron-treated groups, P > 0.10, nonsignificant. In
trial 2a, the BILAT-B cut-saline group's Imb intake was
significantly less than the other groups on day 1.
Therefore, it is interesting that in trial 2b, tropisetron increased Imb intake in the BILAT-B cut group (Fig. 6) to a level that
did not differ from the other tropisetron-treated groups. Over the next
7 days (days 2-8), the consumption of Imb by the five
tropisetron-treated groups was similar (group effect, P > 0.10, nonsignificant; data not shown). Body weights differed among the
tropisetron-treated groups over the 8 days they were eating Imb,
P < 0.01, due to the BILAT-B cut group.
Interestingly, in view of the lower body weight in the BILAT-B cut
group after eating the basal diet, post hoc analysis showed that when
eating Imb on days 3 through 8, the BILAT-B
cut-tropisetron group's body weight was significantly (P < 0.01) greater than the sham-tropisetron group (data not shown).
Trial 2c: BILAT-B cuts and dorsal trunk vagotomies: effect of surgery. On day 1, the cumulative Imb intakes of the saline-treated groups did not differ (effect of surgery: P > 0.10, nonsignificant; data not shown) at any interval. Beginning on day 2, the BILAT-B cut-saline group's 24-h Imb intake, expressed as a percentage of basal-diet baseline, was higher than the other saline-treated groups. This significant (P < 0.05) difference continued over days 4-6, during the period of adaptation to Imb (repeated-measures effect of surgery: P < 0.008). By day 4, the BILAT-B cut-saline group was consuming 83.7% of its basal diet-baseline intake, which was significantly more than both sham groups. This result is consistent with the body weight data from trial 2a, but it differs from the Imb intake data in that trial.
Effect Of Tropisetron
The drug effect over time was significant (P < 0.0001) due to the effect of tropisetron on day 1. Again, the sham-tropisetron and dorsal trunk cut-tropisetron groups similarly increased their cumulative Imb intake above the saline-treated groups during the 6- to 24-h intervals (P < 0.003) as expected, data not shown.On day 2, when the tropisetron effects were no longer seen, the sham-tropisetron group decreased its Imb intake to 29.8% of its basal-baseline intake, which was not different from that for the sham-saline group. The sham-tropisetron group's Imb intake was significantly lower than all the other groups on day 3 (P < 0.03). This is occasionally seen, in our experience, if the animals eat a great deal of Imb on day 1 for any reason. Apparently, when the drug effects are no longer seen and the animals do recognize the effects of Imb, they seem to tolerate it less well for a day or so. By day 5, the sham-tropisetron group's Imb intake was no longer depressed, and there were no differences among the tropisetron-treated groups throughout the remaining days.
Summary Of The Effects Of Total And Selective Vagotomies
As outlined in Table 1, increased Imb intakes and body weights (taken during Imb feeding) were seen with the following cuts: TVAGX, ventral trunk, hepatic + ventral gastric branch, and hepatic + ventral gastric branch + dorsal trunk. Cuts of the dorsal gastric + hepatic vagal branches produced an intermediate result in which the Imb data did not differ significantly from either the sham group or the TVAGX group. No changes in body weights or food intakes were seen on day 1 with cuts that did not include at least the hepatic and one of gastric branches. Increased adaptation over days 2-7 or 8 was seen only in groups with ablation of the hepatic branch. Results with the bilateral cuts sparing only the hepatic branch were inconsistent, but they did include observations of decreases in body weight and both basal- and Imb-diet intakes, again showing interactions among the various vagal branches.
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DISCUSSION |
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|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
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These studies confirm and extend previous work of these and other laboratories in the Imb model. The anorectic response to Imb was seen uniformly as expected (18). We have again shown that the vagus nerve (37) and a 5-HT component that appears to be mediated by the 5-HT3 receptor (17, 22) are integral to this model. Previous studies had determined the presence of 5-HT3 receptors on both vagal afferent fibers (29) and vagal efferents (1); it is clear that 5-HT has important effects on vagal function. Taken together, these findings suggest that the vagus nerve may interact with the 5-HT3 system in mediating Imb anorexia as we reported earlier (37), but it had not been determined previously which branches of the vagus or which innervated structures are important in these effects.
Effect Of Surgeries On Initial Imb Intake
As noted above, TVAGX above the hepatic branch enhances intake of an Imb diet after day 1 on the diet (37). We observed an equivalent increase in Imb intake in rats within the first 6 h of experiment 1 after either TVAGX or the surgeries that included ablation of the hepatic and at least one of the gastric branches. The data for the groups having TVAGX, ventral trunk cut, hepatic + ventral gastric branch cuts, hepatic + ventral gastric branch + dorsal trunk cuts, and hepatic + dorsal gastric branch cuts in the selective vagotomy experiment were very similar (experiment 2, trials 1a-1c). These results suggest that the hepatic and gastric branches are the crucial aspects of the vagus nerve during this period of the responses to Imb on day 1, and they support our observation that the crucial fibers in the ventral trunk travel through the hepatic and ventral gastric branches and do not require the accessory celiac connection. The data also indicate that if only one of the critical connections is severed, the other pathway carries sufficient information for the normal anorectic response to Imb. It should also be noted that the combination of ventral gastric + dorsal gastric branch cuts had no effect. Only when the hepatic branch and at least one of the gastric branch pathways were both disrupted was the animal's feeding response to the Imb ameliorated. Importantly, other combinations of cuts (Table 1) were ineffective on either body weight or Imb intake. These findings suggest that, during the initial responses to Imb on day 1, the specific combination of the hepatic branch and the gastric branches and their innervated structures, including the distal stomach and the proximal duodenum (5), may play a previously unappreciated role in the aminoprivic model. We conclude that the distal stomach and/or the proximal duodenum are the important gastrointestinal structures in the responses to Imb.The effects of TVAGX as well as of the selective cuts used in these experiments appeared between 3 and 6 h, consistent with a role in phase 2, development of the conditioned taste aversion, rather than phase 1, the initial recognition phase, which occurs during the first 3 h (14). If the information about dietary amino acids that are absorbed at the level of the proximal duodenum is important in the early development of a learned aversion to Imb, it appears that the hepatic branch plus at least one of the gastric branches may cooperate to carry that information.
Among results for selective cuts of the ventral branch below the hepatic branch in experiment 2, the BILAT-B cut groups, in which only the hepatic branch was intact, displayed reduced body weight after surgery, even before eating Imb. This suggests that there were metabolic disturbances induced by removal of all the vagal branches except the hepatic branch. This implicates an inhibitory effect caused by the loss of the other vagal branches that may feed back onto the hepatic branch afferents in the intact animal. The observation that these groups lost weight on the basal diet in the absence of a decrease in food intake (e.g., experiment 2, trial 2a) also suggests altered metabolism after this surgery. The body weight losses in the BILAT-B cut groups cannot be explained by alterations in gut motility, because TVAGX groups, which also had the branches to the stomach and small intestine cut, did not show decreases in body weight with the powdered diets used in our protocol. Alternatively, the hepatic branch may play an inhibitory role in the regulation of Imb intake, because all of the surgeries in which the hepatic branch (with or without other branches) was cut enhanced adaptation to Imb in the later responses (days 3-7), as observed previously by Bellinger et al. (4). However, neither total liver denervation, denervation of the hepatic artery, nor hepatic branch cuts alone had an effect on Imb intake on day 1 (2). The altered metabolism apparent in the animals with only hepatic branch spared (BILAT-B cut groups) complicates the interpretation of a selective effect for the hepatic branch in the early (phase 2) responses to Imb. Still, taken together, the results of the BILAT-B ablation surgeries, which included denervation of both gastric branches along with the accessory celiac and celiac branches, supported our previous observations that neither the dorsal trunk cut, the ventral gastric branch cut, nor accessory celiac + celiac branch cuts alone antagonized Imb anorexia, at least on day 1.
Tropisetron Effects
The rat's earliest behavioral responses to Imb are reduced intake of Imb diet and development of a preference for almost any alternative diet (33). It has been suggested that ingestion of Imb causes a conditioned taste aversion via gastrointestinal malaise. Clearly, conditioned taste aversions are seen readily with Imb; however, not all conditioned taste aversions are associated with gastrointestinal malaise. Some conditioned taste aversions are blood borne. Still, the mechanism of nausea may be related to 5-HT release from the enterochromaffin cells in the gut mucosa where 5-HT3 receptors on vagal afferents are activated (24). Vagal mucosal afferents respond dose dependently to 5-HT (8). Repeated mucosal stimulation readily activates vagal afferents and is blocked by 5-HT3 antagonism (8). Antagonism of 5-HT3 receptors with tropisetron blocks cisplatin-induced emesis in the ferret (9). Still, whether the conditioned taste aversion to Imb is mediated by gastrointestinal malaise, the increased intake of Imb after TVAGX on day 1 is not as great as the increased Imb intake seen after tropisetron, and there are temporal differences in the aversive responses after the two treatments (12). Tropisetron also consistently attenuates Imb anorexia in intact animals to ~80% of low-protein diet baseline, a 30% increase over controls, as do both of the selective 5-HT3 antagonists ondansetron and MDL 72,222 (17, 22). Moreover, both tropisetron and MDL 72,222 block the conditioned taste aversion to saccharin after ingestion of saccharin-containing Imb diets (35). Although tropisetron also has effects at the 5-HT4 receptor that may be seen before 6 h (discussed in detail in Ref. 12), it seems clear that the effects of Imb involve the 5-HT3 receptor, at least between 6 and 24 h when the conditioned taste aversion develops, i.e., phase 2.In the present studies, we asked which transections of the vagal nerve branches would interfere with the effectiveness of tropisetron. Observations by Washburn et al. (37) and Pavelka et al. (26) show a significant blunting of the tropisetron effect in the TVAGX group during day 1. In the present study, a trend was revealed consistent with these results, showing that at 6 h the tropisetron effect was blunted by TVAGX and at 9 h by the dorsal trunk cut. However, we were unable to replicate this decreased tropisetron effect in a separate group of dorsal trunk-lesioned rats (trial 2c), and by 24 h, the TVAGX group was responding maximally to tropisetron in that trial. The effectiveness of tropisetron was not blunted either by the celiac + accessory celiac cut or the individual dorsal trunk lesion. Therefore, we suggest that the dorsal trunk of the vagus does not serve alone as an important mediator of tropisetron action. Individual and combination cuts of the hepatic branch, the accessory celiac, and the ventral gastric branch also did not reduce the tropisetron effect, and thus the ventral trunk also may not act alone in mediating the action of tropisetron in this model. Apparently, both the ventral and dorsal trunk are required for the maximum tropisetron effect.
It should be noted that in the absence of subdiaphragmatic vagal fibers, even where we did see a blunting of the response to tropisetron, the drug still significantly increased Imb intake. Therefore, tropisetron may also be acting at extravagal sites, centrally or peripherally, as reported by Daughters et al. (11). Possible alternative pathways for tropisetron's peripheral action include enteric neurons (19) and splanchnic fibers. Splanchnic nerves contain afferent and efferent fibers that are known to influence feeding behavior (34); these nerves may also be involved in the rat's response to Imb. Bilateral cuts of the greater splanchnic nerve did not blunt the tropisetron effect, and they did not increase Imb intake (25). However, Pavelka et al. (26) showed that ventral vagal trunk cuts (including hepatic branch cuts) combined with splanchnicectomy decreased the tropisetron effect on Imb intake similar to the results of the ventral trunk cut in experiment 1. Also, the ventral-B cut, which spares the hepatic branch, combined with splanchnicectomy eliminated the tropisetron effect at 3 h, attenuated it at 6 h, and had no effect at 12 or 24 h, whereas ventral-B cuts without splanchnicectomy did not alter the tropisetron effect at any time point in the present study (experiment 2, trial 2b). Although cisplatin-induced emesis is reduced by vagotomy in ferrets, surgeries combining vagotomy and splanchnicectomy abolish emesis (23). Splanchnectomies alone do not inhibit cisplatin-induced emesis (23). Therefore, neural information carried by the splanchnic nerves together with the ventral vagal trunk, for which anatomic evidence has been provided (7), may explain why vagotomy alone does not attenuate Imb anorexia as effectively as tropisetron.
Adaptation To Imb Diets
After the drug effects had diminished on day 2, both TVAGX and groups in which the hepatic branch was ablated had elevated Imb intake. The hepatic branch has been implicated in increasing adaptation to Imb diets on days 3-7; partial and total liver denervations by Bellinger et al. (2, 4) accelerate the adaptation to Imb during that period. The body weight data for the hepatic + gastric branch cuts and the ventral trunk-lesioned groups of trials 1a-1c exhibited similar patterns of adaptation. In addition, because a transection of the celiac and accessory celiac branches (experiment 2, trials 2a and 2b) did not affect Imb adaptation, but the hepatic + gastric branch or ventral trunk cuts did, similar to the results of Bellinger et al. (4), the increased adaptation seems likely to be due to the loss of the hepatic branch. It is clear that the elimination of the dorsal trunk alone had no effect on Imb adaptation (experiment 1, experiment 2, trial 2c). Results for the longer-term effects in the BILAT-B cut groups (in which the hepatic branch was spared, but the accessory celiac and ventral gastric branches and the dorsal trunk were eliminated) were mixed, but we did not see consistent increases in adaptation in this group with an intact hepatic branch. Taken together with previous results (4), the data presented here support a role for the hepatic branch alone in the adaptation phase of the responses to Imb.In summary, the Imb model (also known as the aminoprivic model) depends on vagal innervation for the full expression of its anorectic effects. The postingestive responses to Imb do not seem to require either the dorsal trunk or the accessory celiac branch of the ventral trunk. At least one of the gastric branches and the hepatic branch apparently can work together to mediate phase 2 of the initial Imb anorexia. These two vagal branches mediate impulses arising at the level of the proximal duodenum, as demonstrated by Berthoud et al. (5), and this area of the gastrointestinal tract responds more vigorously to amino acids than either to glucose or isosmotic saline (32). Further work is indicated to determine whether this area of the gastrointestinal tract plays a hitherto unrecognized role in the aminoprivic model. We cannot presume that these branches are the only ones to carry fibers that respond to Imb. As noted above, the dorsal gastric branch may be able to substitute for the ventral gastric branch in this model, although combinations of the hepatic and both gastric branches were somewhat more effective. Indeed, the many branches of the vagus are so diffusely distributed throughout the abdominal viscera that complex interactions are inevitable. Nonetheless, the loss of certain vagal fibers, especially the hepatic branch and the gastric branches, that innervate the proximal duodenum (5) did appear to diminish the aversion to Imb, although the hepatic branch may have a unique role in the later adaptation phase of the responses to Imb. In contrast, the effect of tropisetron appears to be mediated by extravagal as well as vagal structures.
Perspectives
In past years, the central nervous system has been thought to be the exclusive mediator of the responses to Imb. Carotid infusions and central injections of the limiting amino acid restore food intake in animals ingesting Imb (reviewed in Refs. 14, 31). The presence of 5-HT3 receptors in the anterior piriform cortex and amelioration of Imb anorexia by central injections of 5-HT3 antagonists (16) give further evidence for a central mechanism. The present studies provide support for peripheral mechanisms involved in the Imb response as well and further indicate that the hepatic and gastric branches mediate at least some aspects of this function. These results implicate the distal stomach and proximal duodenum in the initial aversive responses to Imb. The results of previous studies with the hepatic branch support its role in the adaptive phase. Still, full restoration of food intake has not yet been achieved by manipulation of vagal systems, suggesting that central mechanisms remain important. In the wild, where animals rely on nutrient information to secure appropriate diets for maintenance of energy and growth, the presence of multiple systems provides an adaptive advantage. Further studies of the interactions among central and peripheral systems are needed to reveal the site(s) for integration of these systems.| |
ACKNOWLEDGEMENTS |
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The authors are grateful to Dave Hinds, Judy Yeh, Craig Magee, and Jenny Barrett at University of California, Davis and Connie Tillberg, Gerald Hill, and Priscilla Gillaspie at Baylor College of Dentistry for their expert assistance with these experiments.
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FOOTNOTES |
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The work was supported by National Institutes of Health Grants DK-42274, DK-35747, and NS-33347 and Baylor College of Dentistry Research Funds.
Address for reprint requests and other correspondence: D. W. Gietzen, Dept. of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, Univ. of California, One Shields Ave., Davis, CA 95616.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 16 February 1999; accepted in final form 21 April 2000.
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DISCUSSION
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significant effect of
tropisetron, F1,40= 4.70, P < 0.05. SHAM, sham operation; VENT, ventral trunk cut; DORS, dorsal trunk cut;
TROP, tropisetron. Surgical cuts are diagrammed in Fig. 
significant
tropisetron and * surgery interaction, P < 0.05. B: effects of selective vagotomies on intake of the
corrected diet in experiment 1. Twenty-four-hour corrected
diet intakes on days 8-12 are given as a percentage of
basal-diet baseline. Symbols are the same as in Fig. 
