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.

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.

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.

Destruction of different fiber tracts underlies development of lateral hypothalamic lesion-induced hyperthermia and loss of bombesin-induced hypothermia.

The relative roles of lateral hypothalamic cell bodies and fibers of passage were assessed in the development of lesion-induced hyperthermia and bombesin-induced hypothermia. Electrolytic lesions or discrete fiber transections were combined with intracisternal bombesin injection to show that each of these two thermoregulatory effects involves fibers crossing the borders of the lateral hypothalamus; however, the two effects primarily involve fibers crossing different borders. Thus, the hyperthermia and the abolition of bombesin-induced hypothermia which follow lateral hypothalamic damage appear to result from disruption of separate thermoregulatory pathways.

The metabolic bases for "paradoxical" and normal feeding.

Hexoses infused slowly into the duodenum or hepatic-portal vein reduce feeding. However, hexoses can increase food intake following rapid infusion via either of these two routes. Insulin responses and resultant glycemic changes differ following fast and slow duodenal glucose infusion. This is unlikely to be the primary explanation, because fructose affects feeding but is not a secretagogue of insulin under our testing conditions. In follow-up studies, we infused glucose or fructose into the hepatic-portal vein at the fast or the slow rate, and measured 14C incorporation into liver mitochondria and glycogen, and tritiated water uptake into hepatic lipids. Fast infusion of glucose or fructose increased lipid formation, reducing mitochondrial uptake and glycogen formation, and was associated with hunger enhancement. Slow hexose infusion was associated with substrate uptake into mitochondria and glycogen, with reduced uptake into hepatic fat. These findings all are consistent with the previously observed positive correlation seen between mitochondrial oxidation and satiety (28).

The role of the hypothalamus and dorsal vagal complex in gastrointestinal function and pathophysiology.

A foregone conclusion is that central neural and endocrine control of gastrointestinal functions is based on a complex array of interconnecting brain structures, neurochemical systems, and hormonal modulators. As might be expected, a considerable degree of redundancy is seen not only in the manner in which certain brain structures appear to participate in the regulation of GI functions, but also in the extent to which certain neurotransmitters or brain-gut peptides, when injected centrally, alter these functions. Despite the seemingly ambiguous nature of brain-gut interactions, a picture is beginning to unfold that suggests that GI properties are based on certain reflexes (e.g., vago-vagal). These reflexes, in turn, appear to be influenced by brain structures in a hierarchical manner, not all that dissimilar to the system described by Papez and expanded on by MacLean several years ago. For example, the perceptual or cognitive aspects of both external and internal stimuli are monitored at various brain levels, but obviously higher cortical processes are intimately involved. Aversive events provide sensory information, which is integrated primarily by the limbic system (e.g., amygdala) and translated into the expression of emotional behavior and associated autonomic response patterns. Various hypothalamic structures, in turn, appear most strongly to influence physiological changes associated with aversive events by virtue of the direct connections to the autonomic and endocrine systems. Ultimately, the visceral outcome can be seen as being based on the integrated convergence of information from cortical, limbic, and hypothalamic structures onto medullary nerve nuclei as well as other efferent systems. With respect to animal models of neurogenic or stress ulcer, activity of the dorsal vagal complex and vagal efferents appears to be the final common pathway for pathologic changes in the gut.

TRH stimulation and L-glutamic acid inhibition of proximal gastric motor activity in the rat dorsal vagal complex.

The importance of the dorsal vagal complex (DVC) in the control of gastric motor activity has been previously established by electrical and chemical stimulation of this region. We have further evaluated excitatory and inhibitory influences on motor activity of the gastric corpus by microinjection of L-glutamic acid (GLU) and thyrotropin-releasing hormone (TRH) into the DVC. GLU and TRH were ejected by pressure (20-30 psi) in 1-10 nl vol. from multibarreled micropipettes and intraluminal pressure in the gastric corpus was measured using a manometric catheter placed into the stomach through the pylorus of urethane-chloralose anesthetized rats. Gastric motor activity was monitored while micropipettes were advanced from the surface of the dorsomedial medulla to a depth of 1 mm in 100 micron increments. Microinjections of GLU (1-10 pmol) at depths of 200-600 microns below the surface of the brainstem caused a decrease in tonic intraluminal pressure and amplitude of phasic contractions of the gastric corpus. Injection of TRH (1-10 pmol) at depths of 200-800 microns increased both tonic intraluminal pressure and amplitude of phasic contractions. The responses to GLU (10 pmol) and TRH (10 pmol) were abolished by hexamethonium and vagotomy; atropine abolished the effect of TRH and attenuated that of GLU. It is concluded that GLU evokes only vagally mediated inhibitory effects on tonic and phasic gastric motor activity when microinjected into the DVC. In contrast, injection of TRH at the same loci causes only vagal cholinergic increases in motor activity. Subpopulations of neurons in the DVC may, therefore, be activated by specific neurotransmitters having opposite effects on gastric motor activity.

TRH analogue, RX 77368, injected into dorsal vagal complex stimulates gastric secretion in rats.

Medullary sites inducing gastric acid secretion in response to microinjection of the stable analogue of thyrotropin-releasing hormone (TRH; RX 77368, pGlu-His-[3,3'-dimethyl]-Pro-NH2) were investigated in urethan-anesthetized rats. Gastric acid output was recorded every 2 min through a double gastric cannula constantly perfused with 0.9% saline solution maintained at pH 5.5 using an automatic titrator. Unilateral microinjection of RX 77368 (10-100 ng in 50-nl volume) into the dorsal vagal complex (DVC), the dorsal vagal nucleus and nucleus tractus solitarius, induced a significant dose-dependent stimulation of gastric acid secretion. The peak response occurred within 50 min and lasted over 1 h. Other medullary sites, including the lateral, dorsal, and parvocellular reticular nuclei; the medial longitudinal fasciculus; and the medial cuneate nucleus injected with RX 77368 (10-100 ng), were inactive. The TRH metabolites, TRH-OH and His-Pro diketopiperazine (100 ng), injected into the DVC did not influence gastric acid secretion. The stimulation of gastric acid secretion induced by DVC injection of TRH was abolished by vagotomy. These results demonstrate that 1) the DVC is an important site of action for TRH-induced stimulation of gastric acid secretion, 2) TRH action in the DVC is not secondary to the formation of TRH metabolites, and 3) the effect is expressed by vagal efferent pathways. These findings added to the high concentration of TRH-immunoreactivity and receptors in the DVC suggest a role for endogenous TRH in the regulation of vagal outflow to the stomach.

Mechanisms underlying intracisternal TRH-induced stimulation of gastric acid secretion in rats.

The neurohumoral pathways mediating intracisternal TRH-induced stimulation of gastric acid secretion were investigated. In urethane-anesthetized rats, with gastric and intrajugular cannulas, TRH or the analog [N-Val2]-TRH (1 microgram) injected intracisternally increased gastric acid output for 90 min. Serum gastrin levels were not elevated significantly. Under these conditions the TRH analog, unlike TRH, was devoid of thyrotropin-releasing activity as measured by serum TSH levels. In pylorus-ligated rats, gastrin values were not modified 2 h after peptide injection whereas gastric acid output was enhanced. TRH (0.1-1 micrograms) stimulated vagal efferent discharge, recorded from a multifiber preparation of the cervical vagus in urethane-anesthetized rats and the response was dose-dependent. The time course of vagal activation was well correlated with the time profile of gastric stimulation measured every 2 min. These results demonstrated that gastric acid secretory stimulation elicited by intracisternal TRH is not related to changes in circulating levels of gastrin or TSH but is mediated by the activation of efferent vagal pathways that stimulated parietal cell secretion.

Is there a role for the liver in the control of food intake?

The liver, despite its key place in energy regulation, has been implicated in feeding for only the last 20 yr and this theory is still quite controversial. Information about liver metabolism is transmitted to areas in the brain which receive other information relevant to feeding such as from gustatory and central glucoreceptors. Behavioral studies of feeding in which nutrients or antimetabolites have been infused into the liver are equivocal. However, if one considers the liver as acting in concert with oral factors and the gastrointestinal tract, its role in feeding becomes clearer. Glucose infusion into the liver or oral intake of glucose have small effects on glucose intake by themselves. Combined, these two manipulations interact giving reliable suppression of subsequent glucose intake. Fructose when given peripherally is not metabolized by the brain but is by the liver and can suppress feeding. These and other considerations suggest that the liver is probably important in controlling feeding as part of a sequence of integrated events beginning in the mouth, integrated by the brain, and ending with the appropriate behaviors.

Neurobiologic and psychobiologic mechanisms in gastric function and ulceration.

The initiation and termination of feeding behavior are not fully understood. The stomach has been implicated as one source of signals regulating food intake. The sight and smell of food are potent stimuli to gastric acid secretion and contraction. The mouth, upper gastrointestinal tract and liver contain receptors regulating food intake; afferent information passes into the brain stem and into the brain areas. Lateral hypothalamic lesions abolish feeding, raise the body temperature and basal gastric acid secretion and produce gastric erosions. Vagotomy and administering propantheline bromide abolish the increased acid secretion after such lesions; they also alter the mucosal barrier permitting diffusion of protons into mucosal cells. Several of the neuropeptides via the central nervous system stimulate or inhibit gastric acid secretion through modulation of the autonomic nervous system. Most animal models of gastric erosions are associated with a reduced body temperature. Unknown is whether or not this association is the result of increased levels of thyrotropin-releasing hormone-a potent stimulus to gastric acid secretion and erosion formation when injected intracisternally.

Gastric acid and vagus nerve response to GABA agonist baclofen.

Baclofen [beta-(p-chlorophenyl)-gamma-aminobutyric acid], a lipophilic derivative of GABA, was studied for its effect upon the efferent activity of the left cervical vagus in urethane-anesthetized rats. Baclofen (4 mg/kg, s.c.) produces neural discharges in the multifiber vagus preparation. The time course of vagal activation is well correlated with the profile of stimulation of gastric acid secretion recorded every 2 min. Atropine pretreatment (1 mg/kg) did not modify baclofen stimulation of vagal activity. These results demonstrated that a GABAB receptor agonist stimulates the parasympathetic outflow through mechanisms independent of interaction with muscarinic receptors leading to stimulation of gastric acid secretion.

Ingestive responses to homeostatic challenges in rats with ablations of the anterolateral neocortex.

Because rats with either anterolateral neocortical or lateral hypothalamic (LH) damage initially display similar feeding and drinking deficits and recovery patterns, the possibility that anterolateral neocortical ablations would also produce similar chronic ingestive impairments to glucoprivic and hydrational challenges was examined. In general, rats with anterolateral neocortical ablations exhibited normal feeding responses to food deprivation and glucoprivation induced by insulin or moderate doses of 2-deoxy-D-glucose (2-DG), but their response to a high dose (500 mg/kg) of 2-DG was impaired. These animals also drank normally in response to hypertonic saline injections and following water deprivation, but only if food was available during the test session, results indicating that they drank prandially. Results indicate that although the anterolateral neocortex and LH are anatomically related, these brain regions appear to be functionally dissimilar in terms of the regulation of ingestion.

Influence of sympathectomy on the lateral hypothalamic lesion syndrome.

Sympathetic involvement in the lateral hypothalamic (LH) lesion syndrome was examined. Male rats were surgically or chemically sympathectomized and then given LH lesions. At 24 hr postlesion, lesion-induced hyperglycemia but not hyperthermia was attenuated by splanchnicectomy and celiac ganglionectomy. Hyperthermia but not hyperglycemia was attenuated by adrenal demedullation, adrenalectomy, and neonatal guanethidine treatment. Guanethidine-sympathectomized rats also displayed lower basal temperatures, more perilesion chromatolysis, and severer external symptoms than their controls. No form of sympathectomy affected lesion-induced gastric pathology, plasma gastrin concentrations, or body weight loss. Nor did any sympathectomy influence the recovery of ingestive behavior, daily food intake, the feeding response to 2-deoxy-D-glucose, or body weight maintenance in recovered LH-lesion subjects. These results suggest that sympathetic hyperactivity contributes to some aspects of the acute LH syndrome: Hyperglycemia results from sympathetic outflow to the abdomen, whereas hyperthermia is determined by circulating catecholamines and extraabdominal sympathetic innervation. The results fail to support the hypothesis that chronic increases in sympathetic tone are responsible for the reduced food intake and body weight of the LH-lesion rat.

Guanethidine sympathectomy does not prevent meal-induced increases in the weight or oxygen consumption of brown fat.

The interscapular brown adipose tissue (BAT) of adult rats that were neonatally sympathectomized with guanethidine (GUA) consumed less oxygen but weighed the same as BAT from intact controls. In response to a 2-hr mixed-constituent meal, BAT from sympathectomized and control rats showed similar increases in oxygen uptake and weight. These data suggest that some functions of BAT can be maintained even without sympathetic stimulation.

Suppression of gastric acid secretion by intracisternal bombesin does not require the ventromedial hypothalamus.

Intracisternal administration of the tetradecapeptide peptide bombesin suppresses gastric acid release. Other studies have shown that the ventromedial hypothalamus (VMH) may have an inhibitory role in gastric regulation. To determine if the inhibition of gastric acid secretion by intracisternally administered bombesin is mediated by the ventromedial hypothalamus, bombesin was injected intracisternally in rats with ventromedial hypothalamic lesions. Neither anterior nor posterior VMH lesions altered the effects of bombesin on gastric acid, concentration, volume, total output, or on serum gastrin. The bombesin-induced rise in gastric pH was very mildly attenuated by both lesions. The previous finding of enhanced gastric acid secretion after anterior VMH lesions was confirmed. The results suggest that the VMH is not crucial in the bombesin-induced inhibition of acid secretion.

Fatty acid mobilization to 2-deoxyglucose is blocked by globus pallidus lesions.

Lesions of the lateral hypothalamus or discrete bilateral transections on the lateral border of the lateral hypothalamus disrupt the mobilization of metabolic fuels to intraperitoneal administration of the glucose analog 2-deoxyglucose. To better define the pathways involved in these responses, the effects of globus pallidus lesions on body fuel mobilization were investigated. Globus pallidus lesions blocked the increase in plasma free fatty acids normally caused by 2-deoxyglucose, but did not diminish the concomitant hyperglycemia. The data indicate that a pathway running through the globus pallidus, crossing the dorsoanterolateral hypothalamic border, and turning caudally in the dorsolateral hypothalamus is important in the immediate release of free fatty acids following 2-deoxyglucose administration.

Lateral hypothalamic mediation of hypergastrinemia induced by intracisternal bombesin.

Electrolytic lesions of the lateral hypothalamus (LH), but not of the lateral thalamus, prevented the elevation of serum gastrin induced by intracisternal injection of bombesin in rats. Knife cuts through the lateral or the posterior LH border largely abolished the rise in circulating gastrin induced by intracisternal bombesin. Cuts through the medial LH border partly inhibited the response, whereas cuts through the anterior LH border did not modify peptide action. None of the transections altered basal gastrin levels nor the rise in gastric pH and inhibition of gastric acid output induced by intracisternal bombesin. LH lesions did not modify the rise in serum gastrin induced by intravenous bombesin. These results demonstrate that the gastrin-releasing effect of intracisternal bombesin requires the integrity of fibers crossing the posterior, lateral, and medial borders of the LH and is independent of changes in gastric pH. The LH area is not itself necessary for the expression of the inhibitory action of bombesin on gastric acid secretion.

Lateral hypothalamic lesions or transections block bombesin hyperglycemia in rats.

The peptide bombesin-14 causes hyperglycemia when injected into the cisterna magna of rats. We report that acute lateral hypothalamic lesions block bombesin hyperglycemia. Lateral thalamic lesions do not have this effect. We further report that transections on the lateral or posterior borders of the lateral hypothalamus also block bombesin hyperglycemia. Cuts on the medial border also somewhat diminish this hyperglycemia, while cuts on the anterior border are not reliably effective. These results suggest that fibers traversing the lateral hypothalamus are involved in the hyperglycemic response to intracisternal bombesin-14.