The amygdaloid complex, corticotropin releasing factor and stress-induced gastric ulcerogenesis in rats.

The amygdaloid complex and corticotropin releasing factor (CRF) are both important in stress reactions and we thus evaluated the effects of intra-amygdalar CRF on stress ulceration in rats. Bilateral micro-applications of CRF (0.05, 0.5 or 5.0 micrograms) into the central amygdala (CEA) attenuated cold restraint-induced gastric mucosal lesions in a dose-related manner. Similar gastric cytoprotective effects were seen with intra-CEA noradrenaline (NA; 3.0 micrograms), whereas the NA neurotoxin, DSP-4 (25 micrograms), or the beta-adrenoceptor antagonist, propranolol (1 microgram), aggravated stress ulcer pathology. Intra-CEA pretreatment with DSP-4 or propranolol clearly reversed the ulceroprotective effects of CRF during stress. These results indicate that the CEA is a neural substrate for CRF effects, and CRF-NA interactions in this limbic area are crucial for the regulation of stress ulcerogenesis.

Naloxone-sensitive potentiation at granule cell synapses in the ventral dentate gyrus and stress ulcers.

Continuous perfusion of the granule cells in the ventral dentate gyrus with naloxone blocked the long-term potentiation (LTP) induced by high-frequency electrical stimulation of the posterolateral amygdala in freely-moving rats. This treatment also aggravated the stomach ulceration produced by cold restraint. LTP, on the other hand, attenuated the gastric stress pathology. It was suggested that a naloxone-sensitive granule cell gate modulates the impact of environmental stressors.

Stress ulcer modulation by limbic system structures.

A number of studies suggest that the telencephalic limbic system modulates stress ulcer development. The amygdala is assumed to connect sensory experiences, including stressful stimuli, with the emotional reactions and gastrointestinal effects normally produce. The hippocampal formation (entorhinal cortex, dentate gyrus, hippocampus) is part of a gating system, modulating the organism's coping ability. Changes in transmission in this temporal brain region are linked to individual differences in stress ulcer severity. Interactions among "classical" transmitters and several neuropeptides mediate these differences.

The amygdala. Emotions and gut functions.

Studies are reviewed that indicate that the amygdala, and its temporal lobe pathways connecting it with entorhinal cortex and hippocampus, modulates the effects of stressful conditions on the development of gastric pathology. The amygdala integrates aversive stimulus conditions with the defensive behaviors and visceral reactions seen under such circumstances. The transmitter mechanisms for these effects include dopamine, gamma-aminobutyric acid, thyrotropin-releasing hormone, neurotensin, enkephalins, and endorphins. Recording data also show that distinct neural "signatures" in this temporal lobe region correlate with the vulnerability to stressful experiences. The efficacy of synaptic transmission, as represented by potentiation or suppression of recorded neuronal responses, is an indication of coping adjustments, ie, habituation or behavioral helplessness. Glutamate receptors in this brain region, activated by N-methyl-D-aspartate, are implicated in these behavioral strategies. It is proposed that the neurophysiology of these limbic system structures produces individual differences in stress ulcer severity.

The neurobiology of stress ulcers.

We have reviewed the neurobiology of stress ulcers from animal models to potential pharmacotherapeutic mechanisms. The evidence strongly supports the hypothesis that certain stress-related gastric lesions are 'brain-driven' events which may be more effectively managed through central manipulations than by altering local, gastric factors. Recent advances in the use of anxiolytic and antidepressant drugs in the management of stress-related gastric mucosal injury further supports the contention that a brain-gut axis, which may have nervous, peptidergic and classic monoaminergic components, modulates the intricate and complicated pattern of communication between the brain and the stomach. Delineation of the precise pathways which make up this communication as well as their manipulation by various pharmacological agents will be the focus of future research endeavour.

The basolateral amygdala, dopamine and gastric stress ulcer formation in rats.

Bilateral microinjections of dopamine (DA, 0.3, 3.0 or 30.0 micrograms) or the DA-agonist, bromocriptine (3.0 micrograms) into the basolateral amygdala (BLA) dose-dependently attenuated cold restraint stress (3 h at 4 degrees C)-induced gastric ulcer formation in rats. On the other hand, intra-BLA injections of the neurotoxin, 6-hydroxydopamine (10 micrograms) of the DA-antagonist, haloperidol (0.1 or 1.0 micrograms) aggravated such stress ulcer formation. All these effects were seen only when the injection sites were localized in the posterior (and not the anterior) BLA. Further, pretreatment of rats with haloperidol (0.1 micrograms) clearly antagonized the gastric cytoprotective effects of DA or bromocriptine (both at 3.0 micrograms), when both chemicals were injected in the posterior BLA. The results indicate that DA-ergic mechanisms in the posterior BLA are important for the regulation of gastric mucosal integrity during cold restraint stress.

TRH-enkephalin interactions in the amygdaloid complex during gastric stress ulcer formation in rats.

The formation of gastric stress ulcers was studied as a function of interactions between thyrotropin releasing hormone (TRH) and endogenous opioids in the central amygdalar nucleus (CEA) in rats. Bilateral microinjections of TRH (1 or 10 micrograms) into the CEA produced dose-related aggravations in cold restraint stress (CRS, 3 h at 4 degrees C)-induced gastric ulcer formation. Similar stress ulcer facilitating effects were also seen with intra-CEA injections of the opioid antagonists, naloxone (1 or 10 micrograms). On the other hand, the enkephalin analog, D-Ala2-metenkephalinamide (DAMEA, 1, 10 or 20 micrograms) produced dose-dependent attenuations in gastric stress pathology, the effects being most marked with the latter two doses. Pretreatment of rats with intra-CEA naloxone (1 microgram) (a) antagonized the gastric cytoprotective effects of DAMEA (20 micrograms) and (b) further aggravated the ulcerogenic response of TRH (1 microgram), without influencing significantly the TRH (10 micrograms) effect. Further, when DAMEA (20 micrograms) was administered intra-CEA just after TRH (10 micrograms), the stress ulcer facilitating effects of the latter was neutralized. The results indicate that TRH-enkephalin interactions are possible at the level of the CEA during CRS-induced gastric ulcer formation.

Hippocampal pathway to the amygdala and stress ulcer development.

The objective of the first study was to localize the reported aggravation of stress ulcers found after large bilateral hippocampal lesions in rats. Lesions in the ventral hippocampus produced a similar increase in the severity of gastric erosions after cold-restraint, as was seen after large bilateral lesions. Dorsal hippocampal damage produced no differential effects. In the second experiment, high-frequency electrical stimulation of the ventral CA1 region of the hippocampus, a procedure known to induce long-term potentiation, increased the evoked potentials in the lateral central nucleus of the amygdala, and in adjacent parts of the lateral and basolateral nuclei. The increase in the efficacy of synaptic transmission in this pathway attenuated stress ulcer development. It was concluded that the ventral hippocampus is part of a coping system, and a strengthening of synaptic connections with the central amygdala increases the coping ability of rats under stress conditions.

Potentiation of inputs from the posterolateral amygdala to the dentate gyrus and resistance to stress ulcers formation in rats.

Physical restraint was found to increase the activity of a number of multiple units in the lateral amygdala of rats. High-frequency electrical stimulation of units in the posterolateral amygdala increased the amplitudes of granule cell potentials in the dentate gyrus. This bilateral long-term potentiation (LTP) of inputs from posterior areas of the lateral amygdala also attenuated the severity of stress ulcers produced by physical restraint. This effect was reversed by intraventricular injections of the selective N-methyl-D-aspartate receptor blocker, aminophosphonovaleric acid. LTP in this pathway also reduced "struggling" behaviour during restraint. The data were interpreted to indicate that LTP in this temporal lobe pathway increased the coping ability because of faster habituation to stressors.

Effects of intra-amygdalar thyrotropin releasing hormone (TRH) and its antagonism by atropine and benzodiazepines during stress ulcer formation in rats.

Bilateral intra-amygdalar (i/am) microinjections of TRH (1 and 10 micrograms) and physostigmine (10 micrograms) into the central nucleus (CEA) aggravated cold restraint stress (3 hr at 4 degrees C) induced gastric ulcer formation in rats, whereas atropine (1, 5 and 10 micrograms) attenuated this phenomenon. Similar stress ulcer reducing effects were seen with chlordiazepoxide (CDP, 10 mg/kg, IP) and midazolam (1, 3 and 10 micrograms, i/am). Pretreatment of rats with atropine or CDP antagonized the ulcerogenic effects of both TRH and physostigmine. Further, when administered intra-CEA, midazolam neutralized the effects of TRH in a dose-related manner. These results are discussed in light of TRH-acetylcholine-benzodiazepine/GABA interactions within the amygdaloid complex during stress ulcer formation.

Noradrenergic mechanisms in the central amygdalar nucleus and gastric stress ulcer formation in rats.

Microinjections of noradrenaline (NA, 0.3, 3.0 and 30.0 micrograms) into the central amygdalar nucleus (CEA) produced dose-related attenuations of cold restraint (3 h at 4 degrees C) induced gastric ulcer formation in rats. On the other hand, stress ulcer aggravating effects were seen with beta-adrenoceptor antagonist, propranolol (10 micrograms) but not with the alpha-adrenoceptor antagonist, prazosin (1 and 10 micrograms). Moderate enhancements of gastric stress lesions were also seen with the NA release inhibitor clonidine (1 microgram) and the neurotoxin DSP-4 (25 micrograms). Further, pretreatment of rats with intra-amygdalar (i.am.) propranolol but not prazosin, antagonized and reversed the gastric cytoprotective effects of NA. The results indicate that beta-adrenoceptor-mediated NAergic mechanisms at the level of the CEA are important for the maintenance of gastric mucosal integrity during immobilization stress.

Enkephalin-dopamine interactions in the central amygdalar nucleus during gastric stress ulcer formation in rats.

Intra-amygdalar (i/am) microinjections of the enkephalin analog, (D-Ala2)-Met-enkephalinamide (DAME, 3, 10 and 30 micrograms) into the central amygdalar nucleus (CEA) produced a dose-related, naltrexone-reversible attenuation of cold restraint (3 h at 4 degrees C)-induced gastric mucosal lesions in rats. Similarly, gastric stress ulcer formation was also inhibited by i/am dopamine (DA, 10 micrograms) - an effect which was reversed by the DA-antagonist, clozapine (5 mg/kg) pretreatment. Further, pretreatment of rats with clozapine or the DA-neurotoxin, 6-hydroxydopamine (6-OHDA, 10 micrograms, i/am) clearly reversed and/or antagonized the gastric cytoprotective effect of DAMEA (30 micrograms). The results indicate interactions between enkephalinergic and DAergic systems at the level of the CEA in the maintenance of gastric mucosal integrity during immobilization stress.

Granule cell potentials in the dentate gyrus of the hippocampus: coping behavior and stress ulcers in rats.

Evoked population potentials of the granule cells in the dentate gyrus of the hippocampus were increased in stress-resistant rats and decreased in stress-susceptible rats, as indexed by restraint-induced gastric ulcers. Inescapable, uncontrollable shock stimulation also suppressed granule cell population spikes and interfered with subsequent coping responses when escape was possible, i.e. the so-called helplessness effect. The data were interpreted to indicate that the hippocampus is part of a coping system in stressful situations.

Synaptic efficacy in the entorhinal-dentate pathway and stress ulcers in rats.

High-frequency electrical stimulation in the entorhinal-dentate pathway of male Wistar rats was found to increase the amplitudes of the population spikes recorded from granule cells located in the dentate gyrus of the hippocampal formation. This increase in synaptic efficacy attenuated the gastric ulceration produced by cold restraint. It was suggested that this limbic system structure modulates the ability to cope with environmental demands.

Role of dopaminergic mechanisms in the central amygdalar nucleus in the regulation of stress-induced gastric ulcer formation in rats.

Microinjections (i/am) of dopamine (DA) antagonists, haloperidol or clozapine (1 and 5 micrograms) into the central amygdalar nucleus (CEA) produced dose-related aggravations in cold-restraint (3 h at 4 degrees C) stress-induced gastric ulcer formation in rats. On the other hand, DA (10 micrograms, i/am), its agonist, apomorphine (5 mg/kg, ip) and its precursor, l-Dopa (100 mg/kg, ip) significantly inhibited stress ulcerogenesis. Pretreatment of rats (i/am) with clozapine antagonized or reversed the gastric cytoprotective effects of DA, apomorphine and l-Dopa. The results indicate that the CEA is important for the observed gastric cytomodulatory effects of both centrally and peripherally administered dopaminergic agents during stressful experiences.

The GABA/benzodiazepine receptor complex in the central amygdalar nucleus and stress ulcers in rats.

The effects of bilateral microinjections of chlordiazepoxide and GABA into the central amygdalar nucleus on gastric ulcer formation induced by cold-restraint were examined in chronically implanted Wistar rats. Higher doses of chlordiazepoxide (20 and 30 micrograms/amygdala) significantly reduced stress ulcer development, whereas a lower dose (2.5 micrograms) produced a nonsignificant increase in ulcer severity. A similar dose/response pattern was observed following GABA administration. The benzodiazepine receptor antagonist Ro15-1788, applied to the amygdala, abolished the protective effects of both chlordiazepoxide and GABA. In addition, when Ro15-1788 (10 micrograms) was injected into the amygdala by itself, it aggravated the gastric stress pathology. However, a lower dose (5 micrograms) had an attenuating effect, opposite to the pattern of effects produced by chlordiazepoxide and GABA. The role of the amygdalar GABA-benzodiazepine receptor complex in stressful conditions is discussed.

The effects of buspirone, a selective anxiolytic, on stress ulcer formation in rats.

The effects of buspirone hydrochloride were investigated on the formation of cold-immobilization gastric stress ulcers. Low doses significantly attenuated, while higher doses greatly potentiated gastric stress pathology. The dopamine antagonist haloperidol, and the agonist apomorphine respectively, reversed the buspirone effects. The role of dopamine in the expression of buspirone's effects is discussed, although other transmitter systems may mediate some of the actions of buspirone.

Interactions of thyrotropin-releasing hormone (TRH) with neurotensin and dopamine in the central nucleus of the amygdala during stress ulcer formation in rats.

Bilateral microinjections of thyrotropin-releasing hormone (TRH; 1, 3 and 10 micrograms) into the central nucleus of the amygdala produced a dose-related aggravation of cold restraint-induced gastric ulcers in rats. TRH (10 micrograms) also induced gastric erosions in non-stressed animals. Pretreatment with atropine methyl nitrate attenuated the TRH-induced ulcers in both stress and non-stress situations. TRH (10 micrograms) also antagonized the gastric cytoprotection of intra-amygdalar neurotensin (10 micrograms) and was ineffective in altering the stress ulcer-attenuating effects of dopamine (10 micrograms). Pretreatment with i.p. clozapine, however, prevented the inhibitory effects of dopamine on the TRH-induced aggravation of the gastric stress pathology. The results suggest an interaction of TRH, neurotensin and dopamine in the central amygdalar nucleus during stress, and indicate peripheral cholinergic pathways in the mediation of the ulcerogenic effects of TRH.

Electrophysiological activity in the central nucleus of the amygdala: emotionality and stress ulcers in rats.

Multiple-unit activity in the central nucleus of the amygdala was continuously recorded during 4 hr of restraint stress in rats. Five different activity profiles were found. Two types were associated with stress ulceration: one with increased stomach pathology, and the other with decreased stomach pathology. The same unit profiles were also differentially related to the emotionality characteristics of Wistar-derived rats, as well as to those of the genetically selected lines of Roman high- and low-avoidance rats. The type of profile that had been associated with increased pathology was generally seen in the Roman low-avoidance rats and in the Wistar rats that had been judged to be more emotional, that is, defecated before five "rearings" had occurred in an open-field test. The other unit profile was significantly more frequent in the Roman high-avoidance animals and the less emotional Wistar rats. Low-level electrical stimulation of both types of units produced stomach erosions in all cases. It was concluded that the unit activity in the central nucleus of the amygdala reflects certain emotionality characteristics of rats and also their susceptibility of stress ulcers.