Bidirectional Crosstalk between Stress-Induced Gastric Ulcer and Depression under Chronic Stress

Stress contributes to a variety of diseases and disorders such as depression and peptic ulcer. The present study aimed to investigate the correlation between stress ulcer and depression in pathogenesis and treatment by using chronic stress depression (CSD), chronic psychological stress ulcer (CPSU) and water immersion restrain stress models in rats. Our data showed that the ulcer index of the animals after CSD exposure was significantly higher than that of controls. Depression-like behaviors were observed in rat after CPSU exposure. Fluoxetine hydrochloride significantly reduced the ulcer index of rats exposed to CPSU stress, while ranitidine inhibited depression-like behavior of the animals in CSD group. The ulcer index of rats administered with mifepristone after CPSU stress was markedly reduced compared to CPSU group, although there was no significant difference in the depression-like behavior between mifepristone-treated CSD group and naive controls. We also found that the rats exposed to CPSU or CSD stress displayed a lower level of corticosterone than naive controls, however, the acute stress (AS) group showed an opposite result. Additionally, in order to study the relevance of H₂ receptors and depression, we treated the CSD group with cimetidine and famotidine respectively. The data showed that cimetidine inhibited depression-like behavior in CSD rats, and famotidine had no impact on depression. Overall our data suggested that the hypothalamic-pituitary-adrenal (HPA) axis dysfunction may be the key role in triggering depression and stress ulcer. Acid-suppressing drugs and antidepressants could be used for treatment of depression and stress ulcer respectively. The occurrence of depression might be inhibited by blocking the central H₂ receptors.     

The antidepressant role of dietary long-chain polyunsaturated n-3 fatty acids in two phases in the developing brain

In this work we investigated the effect from fish oil (FO) supplementation, rich in n-3 fatty acids, on an antidepressant effect on adult rats in Phase A (supplementation during pregnancy and lactation) and phase B (supplementation during post-weaning until adulthood). During Phase A, female rats, used as matrix to obtain male rats, were divided in three groups: FO (daily supplemented), CF (coconut fat daily supplemented) and control (not supplemented). Our results showed that adult rats whose mothers were supplemented with FO during Phase A and rats supplemented during phase B demonstrated a significantly decreased immobility time when compared to control and CF groups. There was no difference in neither motor activity nor anxiety behavior in the three groups excluding false positive results. Our results suggest that n-3 fatty acids supplementation during Phases A and B had a beneficial effect on preventing the development of depression-like behavior in adult rats.     

The interrelation between individual behavioral characteristics and the indices of brain energy metabolism in rats]

In rats with active type of behaviour in "open field" and "forced swimming" tests in response to weak stress (handling) both the rate of local blood flow (RLBF) and free oxygen tension level (pO2) in the brain are increased, and in rats with passive type of behaviour RLBF is increased, but the pO2 level is decreased. The character of pO2 level changes in the brain under stress is significantly (r = -0.74, p less than 0.001) connected with the level of depressiveness (time of passive swimming) and is nonsignificantly connected with the level of the motor activity. Indices of the active type of behaviour (the number of crossed squares, rearings, comings out to the center of the field and the time of extinction of the motor activity) positively correlate with succinate dehydrogenase (SDG) activity and negatively with NADH-dehydrogenase (NADH-DG) activity and the index of the passive type of behaviour (time of passive swimming) positively correlates with NADH-DG activity and negatively--with SDG activity.     

Changes in autoregulation of coronary blood flow in rats with various sensitivity to stress

The purpose of work: study of a role of endothelial nitric oxide in development of stress-induced changes in autoregulation of coronary blood flow in rats with various types of behaviour. The experiments were performed on isolated hearts of female-rats, in the "open field" test, depending on the type of impelling and searching activity of animals subdivided into two groups: "active" and "passive". After a 6-hour immobilization stress only in "passive" rats an increase of volumetric velocity of coronary flow; a decrease of an autoregulation index, coronary reserve against the background of intravascular pressure reduction, were found out. The blockade of nitric oxide synthesis in this group completely eliminated the stress-induced decrease of coronary vascular tone and essentially limited the caused by stress dissociation of coronary flow and the contractility function of the myocardium. In blood plasma of "passive" animals the nitrite/nitrate contents was by 55% more than of the "active" rats. After the transferred stress, in "passive" animals the nitrite/nitrate concentration in blood plasma increased by 29% and in "active" rats--by 136%; the absolute values, however, did not differ between the groups. Thus the autoregulation of coronary flow seems to be subject to action of stress in the rats showing a "passive" type of behaviour in the test "open field", and practically does not change in "active" animals; secondly, in spite of the fact that the stress-induced amplification of NO-producing function andothelium of coronary blood vessels is stereotyped in different rats, in "passive" rats, apparently, sensitivity of coronary vessels to nitric oxide is higher than at "active" those.     

Catecholamines,nitrogen oxide,and resistivity to stressor lesions: effect of adaptation to hypoxia

Pronouncement of stress-induced disturbance of searching behaviour (using "open field" test) and stomach ulceration were compared for the first time with activity of the catecholamine system in hypothalamus and striatum and also with activity of the stress-limiting system of nitric oxide (NO) in the rats of two strains August and Wistar, which differ in their resistance against stress-induced cardiovascular disorders. The effect of prior adaptation to hypobaric hypoxia on these disorders was also studied. August rats appeared to be more resistant than Wistar rats against stress-induced disturbance of the searching behaviour and stomach ulceration. Results of measuring the content of catecholamines in brain structures and the content of NO stable metabolites nitrate/nitrite in plasma suggested that these differences could be due to the stress activation of the nigro-striatal dopaminergic system in August rats, which was not observed in Wistar rats, and also to the higher production of NO in August than in Wistar rats. Adaptation to hypoxia considerably restricted these stress disorders in rats of both strains. Importantly, the protective effects were associated with activation of the nigro-striatal dopaminergic system in all the animals. In the result, adapted Wistar rats, as distinct from non-adapted Wistar rats, displayed a stress activation of this system. The protective effects of adaptation were also accompanied by an increased NO synthesis. Taken together, the data suggest an important role of the responsiveness of the brain dopaminergic system and NO system in the mechanism of resistance against stress-induced disturbances.     

Transient gastric irritation in the neonatal rats leads to changes in hypothalamic CRF expression, depression- and anxiety-like behavior as adults

Aims

A disturbance of the brain-gut axis is a prominent feature in functional bowel disorders (such as irritable bowel syndrome and functional dyspepsia) and psychological abnormalities are often implicated in their pathogenesis. We hypothesized that psychological morbidity in these conditions may result from gastrointestinal problems, rather than causing them.

Methods

Functional dyspepsia was induced by neonatal gastric irritation in male rats. 10-day old male Sprague-Dawley rats received 0.1% iodoacetamide (IA) or vehicle by oral gavage for 6 days. At 8–10 weeks of age, rats were tested with sucrose preference and forced-swimming tests to examine depression-like behavior. Elevated plus maze, open field and light-dark box tests were used to test anxiety-like behaviors. ACTH and corticosterone responses to a minor stressor, saline injection, and hypothalamic CRF expression were also measured.

Results

Behavioral tests revealed changes of anxiety- and depression-like behaviors in IA-treated, but not control rats. As compared with controls, hypothalamic and amygdaloid CRF immunoreactivity, basal levels of plasma corticosterone and stress-induced ACTH were significantly higher in IA-treated rats. Gastric sensory ablation with resiniferatoxin had no effect on behaviors but treatment with CRF type 1 receptor antagonist, antalarmin, reversed the depression-like behavior in IA-treated rats

Conclusions

The present results suggest that transient gastric irritation in the neonatal period can induce a long lasting increase in depression- and anxiety-like behaviors, increased expression of CRF in the hypothalamus, and an increased sensitivity of HPA axis to stress. The depression-like behavior may be mediated by the CRF1 receptor. These findings have significant implications for the pathogenesis of psychological co-morbidity in patients with functional bowel disorders.     

The role of the lateral and medial hypothalamus in reproducing food and escape instrumental reactions]

In experiments on two dogs it has been found that testing electric stimulation of the lateral hypothalamus reproduces instrumental movement in case of elaborated alimentary instrumental conditioned reflexes (CR) to a tone and does not reproduce it at elaborated acid-defensive instrumental CR. Under testing electric stimulation of the medial hypothalamus the instrumental movement practically is not reproduced neither in alimentary nor in defensive situation. Appearance of instrumental movement at LH electro-stimulation in alimentary situation is connected with activation of backward conditioned connection from motivation "alimentary" LH centre to representation of this movement in the motor cortex.     

Characterization of depression-like behavior in prenatally stressed female rats during ovary cycle

The aim of the present work was a comparative analysis of dynamics of depression-like behavior in prenatally stressed and non-prenatally stressed female rats in the key phases of the ovary cycle. It was found that non-stressed female rats demonstrated high level of depression-like behavior in proestrous phase as compared to the diestrous phase, whereas these rats showed low level of depression-like behavior in estrous phase in Porsolt's test. On the contrary, there were no significant differences in extent of depression-like behavior between prenatally stressed rats in the diestrous and proestrous, although in the phase of estrous in these animals an increase in level of depression-like behavior was noted. Thus, the results of this study indicated pronounced effects of prenatal stress on the character of depression-like behavior of females in different phases of ovary cycle. This study revealed leveling and reversed action of prenatal stress on depression-like behavior in key phases of sexual cycle in female rats.     

Functional transswitching of dominant motivation in the systems organization of behavioral acts

In experiments on rabbits, instrumental and complex conditioned alimentary behaviour was studied at various ways of raising alimentary motivation to extreme levels. Animals behaviour in these conditions could acquire an outwardly non-motivated (in relation to alimentary need) character. It is suggested that these phenomena are based on the transformation of the dominant motivation and not on the mechanism of "shifted" activity. In experiments on rats, a long "pseudoreinforcement" of extremely enhanced motivation of thirst by ethanol led to profound changes of physiological and neurochemical properties of the primary drinking motivation centres of the hypothalamus. It is suggested that such changes underlie the realization of plasticity properties of the dominant motivation.     

Effect of an enkephalin-like tetrapeptide on the food instrumental behavior of rats

An enkephalin-like tetrapeptide (subcutaneous, intraperitoneal and intraventricular injections) disturbs the goal-oriented food instrumental behavior of rats by decreasing the number of adequately performed instrumental reactions. In addition to these disorders, intraventricular microinjections entail an increase in the number of inadequate, incomplete behavioral reactions. Besides, injection of the tetrapeptide evokes specific disorders of motor activity, which manifest in the occurrence in rats of stretches, "duck-like step", motor stereotypy, arching of the tail, changes in the tone of abdominal muscles, etc. The tetrapeptide effects described were not inhibited by narcan, remaining unchanged for 3.5-5 months following a single injection of the tetrapeptide.     

The respiration and oxidative phosphorylation of the brain mitochondria in rats with different types of behavior]

Respiration and oxidative phosphorylation of brain mitochondria were studied in outbred rats with different types of behaviour in open-field test and in forced swimming test. It was found that in rats with "active" type of behaviour (with high locomotor activity and low level of depressiveness) the brain mitochondria have at succinate oxidation a higher rate of respiration in active metabolic state and in presence of uncoupler 2,4-DNP, and a higher rate of ADP phosphorylation than in rats with "passive" type of behaviour (with low locomotor activity and high and moderate levels of depressiveness). Thus rats with active type of behaviour have a higher succinate oxidase activity than rats with passive type of behaviour. It is supposed that revealed differences in brain energy metabolism may affect the dominance of certain type of behaviour.     

THe selective effect of neuroleptics on a dopamine-dependent behavioral disorder in rats in the extrapolation escape test

The low doses of neuroleptics restored the ability of 1-DOPA treated rats to escape behaviour from acute stress situation (in the extrapolation escape test). Non-antipsychotic benzamides and phenothiazine, antidepressants and benzodiazepine tranquilizers were inactive. On the whole, the effectiveness of neuroleptics was in accordance with clinical data. The loss of ability to escape in 1-DOPA treated rats was accompanied by stereotypes hyperlocomotion in the water. Various psychotropic drugs decreased only hyperactivity without the influence on escape behaviour. Both forms of behavioral pathology were prevented by central aromatic acid decarboxylase inhibitor. However, the loss of ability to escape behavior only is selective and sensitive to neuroleptics action.     

Male–female evolutionary game on mate-locating behaviour and evolution of mating systems in insects

We present a model of a male–female evolutionary game on mate-locating behaviour. Two major mating systems are considered: "lek polygyny" (in which males aggregate to wait for females searching for males) and "searching polygyny" (in which males search for females emerging or waiting for males). The model predicts that lek polygyny is favoured (i) when male survivorship during lekking is sufficiently higher than that during mate searching, (ii) when female survivorship while visiting a lek is sufficiently higher than at the emergence site, or (iii) when searching efficiency is higher at a lek than at an emergence site. Furthermore, the model shows that a reduction in the reproductive value of females later in the day, which prevents males from performing riskier mate-locating behaviour, can result in a change of mating system. In addition, mixed mating systems can be realized as transient states during this shift.     

Role of the Amygdala in Antidepressant Effects on Hippocampal Cell Proliferation and Survival and on Depression-like Behavior in the Rat

The stimulation of adult hippocampal neurogenesis by antidepressants has been associated with multiple molecular pathways, but the potential influence exerted by other brain areas has received much less attention. The basolateral complex of the amygdala (BLA), a region involved in anxiety and a site of action of antidepressants, has been implicated in both basal and stress-induced changes in neural plasticity in the dentate gyrus. We investigated here whether the BLA modulates the effects of the SSRI antidepressant fluoxetine on hippocampal cell proliferation and survival in relation to a behavioral index of depression-like behavior (forced swim test). We used a lesion approach targeting the BLA along with a chronic treatment with fluoxetine, and monitored basal anxiety levels given the important role of this behavioral trait in the progress of depression. Chronic fluoxetine treatment had a positive effect on hippocampal cell survival only when the BLA was lesioned. Anxiety was related to hippocampal cell survival in opposite ways in sham- and BLA-lesioned animals (i.e., negatively in sham- and positively in BLA-lesioned animals). Both BLA lesions and low anxiety were critical factors to enable a negative relationship between cell proliferation and depression-like behavior. Therefore, our study highlights a role for the amygdala on fluoxetine-stimulated cell survival and on the establishment of a link between cell proliferation and depression-like behavior. It also reveals an important modulatory role for anxiety on cell proliferation involving both BLA-dependent and –independent mechanisms. Our findings underscore the amygdala as a potential target to modulate antidepressants'' action in hippocampal neurogenesis and in their link to depression-like behaviors.     

MIF-1 potentiates the action of tricyclic antidepressants in an animal model of depression.

In the present paper, the effect of simultaneous treatment of rats with low doses of MIF-1 and tricyclic antidepressants on rat behavior in the forced swim test was studied. It was found that MIF-1 stimulated in a dose-dependent manner "active" behavior of animals in this paradigm. The effect of MIF-1 appeared to be independent of changes in rats' locomotion in the open field test. The combined treatment of rats with MIF-1 (0.01 mg/kg IP) and amitriptyline (5 mg/kg IP) or desipramine (1.25 mg/kg) IP) significantly stimulated active behavior in the forced swim test above the level obtained with each of the drugs given separately. The present data suggest the potential clinical efficacy of a combined therapy of depressive patients with MIF-1 and small doses of tricyclic antidepressants.     

The choice of reinforcement quality depending on the delay time of the instrumental reaction in cats]

In experiments on seven cats instrumental delayed reflexes with different quality reinforcement were elaborated by method of "active choice", where the time of delay of the motor reaction served as a signal of quality of the reinforcement. Five cats used a strategy with long delay high-quality reinforcement (meat), and two cats preferred short delay and low-quality reinforcement (bread-meat mixture). In special experiments with the change of alimentary motivation (24-hour alimentary deprivation and saturation of animals) it was established that the level of alimentary motivation within the studied limits did not change the strategy of behaviour preferred by the given animal. Individually varying ability to choice of reaction determining more valuable reinforcement it is possible to consider as an experimental analogue of the mechanisms of will. The question is discussed about the role of typological properties of cats in choice of behaviour strategy.     

Changes in innate forms of motor behavior in rats during long-term hypokinesia

The structure of motor behaviour in response to environmental tests--"open field" and "with-a-partner" situation (according to P. V. Simonov)--was studied in rats after 1, 3 and 6 weeks of hypokinesis, (to K. Hecht), as compared to the control. In control animals a relatively low level of orienting-investigation reactions and of grooming was observed as well as a low alimentary activity, which is considered as a manifestation of innate passive defensive reactions in the above situations. Disappearance of these reactions in the course of hypokinesia has two stages: predominant increase in orienting-investigating reactions (1-3 weeks); their subsequent decrease and an increase in the grooming (after 6 weeks). The relation between innate and conditioned behavioural changes is discussed as well as stability of alimentary behaviour in rats.     

Asymmetry of movement direction as a tactic in the feeding behavior of rats

The sign and degree of spatial-motor asymmetry in rats were studied in conditions both of spontaneous or signalled choice in an U-maze and spontaneous multiple choice in a radial labyrinth. It was shown that during investigation of a new environment, motor asymmetry in rats was feebly expressed in all conditions of experiments, irrespective of the labyrinth scheme and experimental procedures. In the process of training, adequate behaviour was formed and in some conditions a distinctly expressed spatial asymmetry appeared, while in other cases it was absent. Apparently, while investigating an "unknown" situation (where rats can move rightwards and leftwards), the strategy of "displacement" is characteristic of them. Later the rate of asymmetry manifestation depends on concrete spatial and temporal characteristics of already "familiar" surroundings.     

Individual characteristics of spontaneous locomotor activity and adaptive behavior in the rat

Spontaneous locomotor activity (SLA) of the male rats possesses significant individual differences. The daily volume of this activity is sufficiently stable for each separate individual. Animals with high and low SLA also differ in daily dynamics of this parameter. The behaviour of the rats with low SLA was characterized by lesser orienting activity and greater emotional reactivity in comparison to the rats with high SLA. By means of factor analysis it was established that, along with searching activity, emotional reactivity and alimentary motivation, the need in motor activity is one of the main inner factors, determining various manifestations of adaptive behaviour.     

Behavioural evidence for simultaneous dual changes of 5-HT receptor subtypes: mode of antidepressant action?

Effects of the classic antidepressant imipramine and of an imipramine-like potential antidepressant dihydroergosine were studied in mice, rats and guinea pigs using behavioural models associated with the activation of 5-HT2 and 5-HT1 receptors respectively. Both drugs given in a single dose inhibited the 5-HT2 mediated behaviour for 24 and 48 h respectively and simultaneously stimulated 5-HT1 mediated behaviour for 6 days. Blockade of 5-HT2 receptors could have reduced their inhibitory influence on 5-HT1 receptors. We propose that the interplay between the two receptor subtypes controls the serotoninergic transmission. This idea throws a new light on the mode of action of antidepressants.