Body temperature and wheel running predict survival times in rats exposed to activity-stress.

The relationship between restricted feeding, core body temperature (Tb), wheel running, survival, and gastric erosion formation was examined in female rats exposed to activity-stress. Core body temperature and gross motor activity were telemetrically monitored in four groups of rats that had free access to running wheels and in one group that was not allowed to run on the wheels. Twenty-four hours prior to the onset of hypothermia and predicted mortality, different groups were left undisturbed, warmed with a heat lamp, denied access to running wheels, or euthanized. Length of survival in wheel-running rats varied from 2 to 12 days. During the first day of food deprivation, premorbid changes in the variability of Tb during the diurnal period and the mean number of wheel revolutions during the nocturnal period were strongly predictive of length of survival. Warming rats with a heat lamp or preventing rats from ever running on the wheel increased the length of survival and attenuated gastric erosion formation. Only rats that were warmed had a greater likelihood of survival. Gastric pathology was also reduced in rats that were euthanized prior to becoming moribund. Rats that were left undisturbed or locked from the running wheel over the last 24 h of testing became moribund and had extensive gastric mucosal damage. These results indicate that thermoregulatory disturbances induced by restricted feeding and not wheel running alone are critical in determining survival and the degree of gastric mucosal injury in rats exposed to activity-stress. Results further suggest that predisposing factors may put some rats at risk for the development of activity-stress-induced mortality.

Effects of intermittent tail shock or water avoidance on proximal colonic motor contractility in rats.

Changes in proximal colonic mechanical activity and defecation during exposure to three different types of experimental stressors were examined in rats chronically implanted with 2 force transducers on the proximal colon. To validate the integrity of the recording system, meal-induced changes in proximal colonic contractility were initially measured in all rats 1-2 days prior to stress induction. Different groups of ad lib fed rats were then exposed to tail shock, re-exposure to the shock chamber or water avoidance for 1 h over the next 1-2 days. Two types of phasic colonic contractions, long (0-3/min) and short (6-8/min) duration, were analyzed separately using a computer. Long duration contractions were significantly elevated 21-71% over fasting basal values from 61-120 min following a meal. No other consistent changes during the prandial or postprandial period were observed. Tail shock significantly suppressed proximal colonic contractility from pre-shock values and increased fecal output and fluid content when compared to ad lib fed rats that were not shocked. Fecal output increased but proximal colonic contractility did not change when previously shocked rats were re-exposed to the tail shock chamber but not shocked. In rats exposed to water avoidance, proximal colonic contractility was minimally suppressed but defecation was significantly greater than home cage control animals. These results indicate that proximal colonic contractile activity is differentially altered by exposure to different environmental stressors and may be a contributing factor in stress-induced bowel dysfunction.

Chronic dietary restriction influences tumor metastasis in the rat: parametric considerations.

Chronic dietary restriction is a well-documented means of inhibiting tumor growth. This study examines the effects of chronic dietary restriction on tumor metastasis in the rat. We investigate the effect of 1) the degree of food restriction, 2) the effect of preexposure to food restriction, and 3) the duration of food restriction after tumor inoculation on tumor metastasis. We also compare two methods of dietary restriction: 1) the time that food is available and 2) the amount of food available. Our findings demonstrate that rats restricted to 50% of ad libitum diet for one week before inoculation with MADB106 tumor cells and for three weeks after inoculation exhibit a significant (p < 0.001) reduction in lung colonization compared with animals fed ad libitum. Animals restricted to access to food for 4 hrs/day (60% of ad libitum) for the same period of time exhibit significantly (p < 0.005) greater lung tumor colonization than animals fed ad libitum. Preadaptation to the feeding regimen for one week before tumor inoculation proved to be critical in inhibiting tumor metastasis. The tumor-inhibitory effect was not significantly influenced by the duration of restriction after inoculation or by the manner in which food restriction was implemented. Finally, we demonstrate that inhibition of tumor colonization may be mediated by enhanced natural killer cell activity in the early postinoculation period.

Effect of acute dietary restriction on the colonization of MADB106 tumor cells in the rat.

The effects of acute food restriction (i.e. 24-72 h) on (1) the colonization of MADB106 tumor cells; (2) the response of specific T cell subsets in peripheral blood (i.e. CD4+ and CD8+ cells), and (3) natural killer cell activity (NKCA) in the spleen were studied in the Fischer 344 rat. Previous studies have demonstrated that the spread of this tumor cell is enhanced by exposure to an acute stressor within 24 h of tumor inoculation. Consistent with these reports, 72-hour food restricton after tumor inoculation enhanced colonization of tumor cells to the lungs when assessed 4 weeks after inoculation. Food restriction was found to markedly influence the percentage of T cell subsets (i.e. CD4+ and CD8+ cells) and NKCA in the early (24-72 h) postinoculation stage. At 72 h after inoculation, food restriction was associated with a significant reduction in the percentage of CD4+ cells in tumor- or saline-inoculated animals. The percentage of CD8+ cells was significantly increased at 24 and 72 h after tumor inoculation in ad libitum, but not in food-deprived animals. NKCA at 72 h was significantly reduced in saline-treated food-deprived animals compared to animals fed ad libitum. Given that glucocorticoids are typically increased during acute food deprivation and that glucocorticoids are in some instances associated with depressed NKCA, the present study investigated whether there was a relationship between plasma glucocorticoid levels (i.e. corticosterone) and NKCA; however, no significant relationship was found. In conclusion, the present findings demonstrate that 72-hour food deprivation is associated with enhancement of tumor metastasis. This outcome is mediated, at least in part, by the modulatory effect of the physiological response to acute food restriction upon the distribution of circulating T cells and NKCA in the spleen during the early (24-72 h) postinoculation phase.

Microinjection of thyrotropin-releasing hormone analogue into the central nucleus of the amygdala stimulates gastric contractility in rats.

The effect on gastric contractility following bilateral microinjection of thyrotropin-releasing hormone (TRH) analog, RX 77368, into the central nucleus of the amygdala was examined in fasted, urethane-anesthetized rats. Extraluminal force transducers were used to measure gastric corpus contractility. Bilateral microinjection of RX 77368 (0.5 microgram, 1.0 microgram, n = 6 each) stimulated gastric contractility for up to 120 min post-injection, P < 0.05. Gastric contractility was not significantly stimulated by microinjection of 0.1 microgram RX 77368, 0.1% bovine serum albumin (BSA) into the central nucleus or RX 77368 (0.5 microgram, 1.0 microgram) into sites adjacent to the central nucleus. Peak responses (1.0 microgram) occurred 40 min post-injection and represented a 16-26-fold increase over basal values. The frequency of gastric contraction waves was attenuated for 0-90 min in rats receiving central amygdaloid microinjection of RX 77368 (0.1, 0.5 or 1.0 microgram) versus rats microinjected with the vehicle or RX 77368 into sites adjacent to the central nuclei. The stimulatory effect of RX 77368 (1.0 microgram) on gastric contractility was abolished by subdiaphragmatic vagotomy. These results indicate that the TRH analog, RX 77368, acts within the central amygdala to vagally stimulate gastric contractility.

Interleukin-1 beta in the dorsal vagal complex inhibits TRH analogue-induced stimulation of gastric contractility.

The effect of murine interleukin-1 beta (mIL-1 beta) microinjected into the dorsal vagal complex (DVC) on thyrotropin-releasing hormone (TRH) analogue (RX-77368)-induced stimulation of gastric contractility was examined in fasted, urethan-anesthetized rats. Gastric corpus contractions were measured with extraluminal force transducers and analyzed by computer. Microinjection of RX-77368 (30 ng) into the right DVC with mIL-1 beta microinjected either into the right (100, 250 pg) or into the left (100, 500 pg) DVC inhibited gastric contractility for 30-120 min postinjection. Peak suppression of gastric contractility (64-78%) occurred at 50-60 min postinjection. Microinjection of mIL-1 beta into the DVC at a lower dose (10 pg) or into sites adjacent to the DVC (100-500 pg) did not suppress the stimulated gastric contractility pattern. Injection of mIL-1 beta (250 pg) or 0.1% bovine serum albumin into the DVC alone did not alter basal gastric contractility. Intracisternal injection of the IL-1 receptor antagonist (250 ng/10 microliters) abolished the inhibitory effect of mIL-1 beta (250 pg) on gastric contractility. These results demonstrate that mIL-1 beta acts in the DVC to inhibit vagally stimulated gastric contractility, and its action is mediated by IL-1 receptors.

Microinjection of thyrotropin-releasing hormone in the paraventricular nucleus of the hypothalamus stimulates gastric contractility.

Changes in gastric contractility following microinjection of thyrotropin-releasing hormone (TRH) into the paraventricular nucleus of the hypothalamus (PVN) were examined in fasted, urethane-anesthetized rats. Gastric contractility was measured with extraluminal force transducers and analysed by computer. Unilateral and bilateral PVN microinjections of TRH (0.5 and 1.0 microgram) significantly increased the force index of gastric contractions from 0 to 60 min postinjection, when compared with animals microinjected with 0.1 microgram TRH, 0.1% BSA or TRH (0.5 and 1.0 microgram TRH) in sites adjacent to the PVN. The gastric force index was also significantly elevated from 61 to 120 min postinjection in rats receiving bilateral PVN microinjections of TRH (0.5 and 1.0 microgram). Peak gastric responses occurred within 10-20 min postinjection and represented an approximately eight-fold increase over basal values. In the remaining groups, the force index was not significantly altered from preinjection values. The excitatory action of TRH (1.0 microgram) on gastric contractility was completely abolished by subdiaphragmatic vagotomy. These results suggest that TRH acts within the PVN to stimulate gastric contractility via vagal-dependent pathways.

Gustatory and olfactory contributions to alcohol consumption in rats.

To determine the relative contributions of taste and smell in the consumption of alcohol by rats, the present experiment tested normal rats (n = 14) and rats with either gustatory cortex ablations (n = 10), olfactory bulbectomies (n = 11), or combination gustatory cortex and olfactory bulb ablations (n = 12). Rats were tested under mild fluid deprivation using a two-bottle testing procedure. Thirteen concentrations of alcohol (0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, and 12%, v/v) were tested in ascending order. Results showed that at strong alcohol concentrations (7% through 11%) rats with combined gustatory cortex and olfactory bulb ablations consumed significantly more alcohol than normal control rats. Rats lacking gustatory cortex displayed a similar increased level of consumption with strong alcohol concentrations. It is suggested that the high level of consumption of strong alcohol concentrations by rats with central nervous system damage reflects an associative deficit rather than an alteration in taste or odor perception.

Effects of amygdaloid lesions on gastric erosion formation during exposure to activity-stress.

To examine the role of the amygdala in the production of gastric ulcers induced by activity-stress, electrolytic lesions were placed in the centromedial (CENT) and medial (MED) amygdaloid nuclei, as well as in the intra-amygdaloid division of the bed nucleus of the stria terminalis (BNST). As compared to sham-operated controls (CONT), gastric ulceration was attenuated in rats with CENT lesions and exacerbated in rats with lesions located in the BNST or MED. Wheel running did not differ significantly between control animals and lesioned rats, but did differ within lesioned groups. Rats with MED lesions ran more than rats with CENT or BNST lesions. Results support the view that the integrity of the centromedial amygdala is critical for the maintenance of the viscera and demonstrate that neurogenic factors contribute to the development of gastric erosions during exposure to activity-stress.

Effects of preadaptation to restricted feeding and cimetidine treatment on gastric mucosal injury and wheel running during exposure to activity-stress.

The relationship between gastric injury and wheel running was examined during an activity-stress (A-S) experiment. In Experiment 1, rats were preadapted to a 1-h restricted feeding schedule for either 0, 15, 25 or 35 days prior to entering activity wheels. All rats preadapted to the 1-h feeding schedule had significantly less gastric damage than rats without any preadaptation experience. Survival of A-S was related to the length of preadaptation experience. Regardless of preadaptation experience, rats increased daily running with the greatest increase occurring during the 6-h period preceding the feeding hour. In Experiment 2, rats were injected twice daily with cimetidine (100 mg, ip) or vehicle during the 6-h preceding the feeding session. Rats treated with cimetidine had less mucosal injury but had no increased survival when compared to rats injected with the vehicle. Cimetidine treated rats had essentially the same running pattern as controls. These results demonstrated that the process of mucosal injury did not stimulate excessive wheel running. The data also suggest that mucosal injury is not related to survival in A-S rats.

Odor cue mediation of alcohol aversion learning in rats lacking gustatory neocortex.

Normal rats presented with a 5% alcohol solution followed by lithium chloride-induced illness quickly learned to avoid drinking alcohol. After training, the rats also avoided drinking water in the presence of the alcohol odor alone, whether tested immediately or 1 month later. In Experiment 1, rats with gustatory neocortex (GN) ablations also developed strong alcohol aversions when the alcohol solution was paired with illness. They also showed normal avoidance of drinking in the presence of the alcohol odor alone when tested soon after training. In Experiment 2, when normal rats were trained to avoid alcohol, given GN ablations, and then tested for retention 1 month later, avoidance of drinking water in the presence of the odor alone was significant but attenuated somewhat in relation to trained control rats. These data support the hypothesis that rats lacking GN partially acquire alcohol aversions by using odor cues and confirm that associative learning is intact in these rats despite the fact that GN rats display significant deficits in aversion learning when only tastes are paired with illness.

Alcohol aversion generalization in rats: specific disruption of taste and odor cues with gustatory neocortex or olfactory bulb ablations.

Rats with ablations of the gustatory neocortex (Experiment 1) and rats with olfactory bulb ablations (Experiment 2) were compared with normal rats for aversion generalization to both single taste solutions (sucrose, sodium chloride, quinine hydrochloride, hydrochloric acid) and compound taste solutions (pairs of the four single tastants) following alcohol aversion training. All rats acquired equal and strong alcohol aversions. Control rats showed consistent aversion generalization to both the sucrose + quinine and the sucrose + hydrochloric acid solutions; no significant generalization occurred to the single tastants except a weak generalization to sucrose in Experiment 2. Rats with gustatory neocortical ablations failed to show aversion generalization to any of the taste solutions. Rats with olfactory bulbectomies displayed the same aversion generalization functions as control rats but exhibited significantly faster extinction of the alcohol aversion than did the trained control rats. Results from the present experiments suggest that during alcohol aversion learning, rats lacking gustatory neocortex use odor cues (no taste generalization), whereas rats lacking olfactory bulbs utilize taste cues (normal taste generalization).