One important role of the brain is to maintain the living organism in a normal steady state by responding adequately to the changing demands of both the internal and external environment of the body. Psychosomatic disorders are perturbed states of this regulatory mechanism. Today, knowledge of neurotransmitters and neuromodulators and their receptors is rapidly increasing. Many amines, such as dopamine, noradrenaline, serotonin and acetylcholine, many amino acids and nucleosides, such as glutamate, GABA and adenosine, and many peptides, such as substance P, enkephaline, endorphine, TRH, CCK and others, act as neurotransmitters or neuromodulators. Psychosomatic disorders are closely related to mental activities like anxiety and depression. These mental activities have their biological basis in the central nervous system. Anxiety disorders are suspected of being caused by a disturbance of endogenous anxiogenic substances. Candidates for these substances include noradrenaline, β-pcarboline and lactate. GABA and adenosine, on the other hand, are putative endogenous anxiolytic substances. In anxiety disorders, anxiety attacks are provoked by the administration of the α_2 adrenoceptor antagonist yohimbine and inhibited by its agonist clonidine, indicating the supersensitvity of presynaptic α_2 adrenoceptors in such disorders. Investigation of the benzodiazepine receptor revealed that the receptor is coupled with GABA receptor sites and associated chloride channels, a result that indicates benzodiazepine facilitates GABA related neuronal inhibition. β-Carboline and its derivatives are active antagonists or inverse agonists of benzodiazepine. Caffeine and theophyline are anxiogenic substances which are antagonists of adenosine. On the other hand, carbamazepine has a high afiinity to the adenosine receptors, especially to the A1 receptor in brain tissue. The anticonvulsive and antianxiety effects of carbamazepine may be related to central adenosine function. Depression is frequently provoked by chronic stress. Among patients with major depression, there are many nonsuppressors of the dexamethasone suppression test (DST), indicating a hyperactivity of hypothalamicpituitaryadrenocortical function. The DST is a state-dependent biological index of the severity of symptoms. Depressed patients with high postdexamethasone cortisol levels have high plasma catecholamine levels. The plasma levels of MHPG (3-methoxy-4-hydroxyphenylglycol), a metabolite of noradrenaline, are also increased in depressed patients, many of whom have symptoms of anxiety and agitation. The various states of psychosomatic disorders are most likely based on different kinds of disturbances in the function of neurotransmitters or their receptors. Increased knowledge of the biological basis of such disorders contributes to their treatment.

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By measuring levels of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxy-phenylethyleneglycol sulfate (MHPG-S0_4) in the rat brain regions, we investigated various characteristics of the brain NA metabolism caused by a variety of stressful stimuli. One hourimmobilization stress caused significant increases in MHPG-S0_4 Ievels in the extended brain regions such as the hypothalamus, amygdala, thalamus, hippocampus, midbrain, cerebral cortex and pons+ medulla oblongata(med. obl.) and most of them accompanied the reductions of NA Ievels. The result suggests that NA release in the brain regions is enhanced by immobilization stress. The study, where probenecid was used to prevent MHPG-S0_4 from being transported from the brain, revealed that these increases in NA release induced by stress exhibited the regional characteristics ; rapid in the hypothalamus, amygdala and thalamus, delayed in the cerebral cortex and hippocampus and continuous in the pons+med. obl. Psychological stress, where the rats were given no electric shock at all, but exposed to the emotional responses which were shown by other electrically-shocked rats, increased NA release preferentially in the hypothalamus, amygdala and locus coeruleus (LC) region. Further, NA release in the hypothalamus, amygdala, pons+med. obl. and midbrain in old rats remains activated by 3-hour immobilization stress for prolonged period of time following release from stress, although increases in NA release in the young rats were recovered to the control levels at that time. Diazepam, a typical anxiolytic drug of benzodiazepines, significantly attenuated immobilizationstress induced increases in NA release in the hypothalamus, amygdala, hippocampus, cerebral cortex and LC region and these effects were antagonized by a specific antagonist of benzodiazepines, Ro 15-1788. The same dose of diazepam significantly attenuated emotional responses of stressed rats such as vocalization and defecation, and these effects were also antagonized by Ro 15-1788. These results suggest that diazepam reveals its anxiolytic action via benzodiazepine receptors by attenuating stressinduced increases in NA release in these regions. Together with these findings, we propose the hypothesis that increases in NA release in such brain regions as the hypothalamus, amygdala, hippocampus and LC region are, in part, closely related to the provocation of fear and/or anxiety and its inhibition by diazepam in these regions to the relief of these emotions of animals exposed to stress.

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SART (repeatedly cold)-stressed rodents have been reported to have a variety of physiological anomalies consisting of continuous hypotension, vagotonia in the small intestine and some arteries, sympathicotonia in the heart, hyperalgesia and so forth. These animals have been recognized as model animals for clinical vagotonictype dysautonomia from the results of the mecholyl test, Aschner's oculocardiac test and others. In this paper, recent findings concerning SART-stressed animals, with special reference to autonomic imbalance, are reported. l. With regard to peripheral tissue blood flow determined by the hydrogen clearance method, SART-stressed mice showed a decrease in the subserous region of the stomach, no change in the liver and an increase in the subcutaneous tissue. This decrease in gastric blood flow but not the increase in dermal blood fiow was blocked by left-cervical vagotomy. When the mice received 6hydroxydopamine, an adrenergic degenerator, tissue blood flow changes elicited by SART stress tended to be reinforced in both the stomach and cutis. 2. In the basal ganglia and hypothalamus, SART stress resulted in decreases in acetylcholine (ACh) content and increases in the activities of choline acetyltransferase and acetylcholinesterase (AChE), whereas it caused increased ACh content and decreased AChE activity in the duodenum. In rats exposed to simple cold stress, only the ACh content of the above brain areas was slightly decreased. Bilateral subdlaphragmatic vagotomy inhibited the above alterations in the duodenum of SART-stressed rats. 3. Several hypothalamic regions of rats were lesioned using a lesion generator. Many abnormal symptoms in SART-stressed rats were prevented to a considerable extent by lesioning of the lateral or anterior part of the hypothalamus, while ventromedial-and posterior-hypothalamic lesioning was revealed to have only slight influence on them. 4. From electrocorticograms (EC_oG_s) in the restingarousal state analyzed according to the power spectra technique, SART-stressed rats were found to exhibit faster waves with lower voltages. By contrast, slowwave sleep EC_oG_s of SART-stressed rats were characterized by their increased amplitude and decreased frequency, compared to normal rats. From the above results, the various disorders observed in SART-stressed animals are suggested to be associated with the function of the autonomic, especially parasympathetic, nervous systems, and also, SART stress-induced peripheral changes are thought to be under the control of the autonomic center. Cholinergic profiles in brain areas, fast dominant waves in EC_oG_s and various other disorders in SART-stressed animals are very interesting symptoms from the standpoint that in clinical cases, cholinergic neurons have been implied to be involved in affective disorders such as depression and mania, Alzheimer's disease and other conditions, and that patients with psychosomatic diseases have been reported to show fast dominant waves in EC_oG_s.

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When the rat was housed individually in an activity-wheel cage on restricted feeding schedule, the running activity increased progressively and some rats died following a sudden decrease of running activity. The majority of rats manifested severe gastric mucosal lesions only inYthe glandular portion of the stomach. Par & Houser (1973) gave these lesions the designation of "activity-stress ulcer". Among the variables affecting the development of activitystress (AS) ulcer the augmentation of running activity on a restricted feeding schedule has been considered to be most important. To my knowledge, however, there has been no other study in which the relation between rhythmicity of running activity and gastric ulceration was clearly demonstrated. We conducted several series of experiments to investigate the etiology of AS ulcer from the chronobiological standpoint. All animals employed were Long-Evans rats. The light-dark cycle in the vivarium was kept constant (light on at 7 : 00 and off at 19 : 00). An activity-wheel cage consisted of a runningwheel and wiremesh cage allowing access to food and water. Revolutions of each running wheel were recorded automatically at intervals of 30 min by an electrical counting system. To pursue a time-dependent change in the gastric mucosal surface, endoscopic observation was applied using an ultra-thin fiberscope. Although rats showed a typical nocturnal running activity during the unrestricted feeding period for habituation, a remarkable deterioration in circadian rhythmicity of running activity was found as a function of the day of restricted feeding ; the ratio of ligh-ttime revolutions to total revolutions per day increased progressively. Periodical endoscopic observations indicated that the deterioration in circadian rhythmicity closely correlated with the course of gastric ulceration. In this symposium, I presented effects of experimental manipulations, which can modify the development of AS ulcer, on circadian rhythmicity of running activity, and discussed the significance of chronobiological approach on the ethiology of AS ulcer in rats.

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Pathophysiological mechanism of irritable bowel syndrome (IBS) was analyzed by experimental psychological stress. The subjects were 30 cases with typical IBS and 20 cases of control. After an electric transducer was inserted in the sigmoid colon for measuring colonic intraluminal pressure, mirror drawing test (MDT) was loaded as psychological stress with examination of various factors of autonomic nervous function and gastrointestinal hormones. Loading with stress interview and autonomic drugs followed it. The results were as follows ; (1) Systolic and diastolic blood pressure and plasma catecholamines elevated significantly during MDT stress in both groups (p<0.05). (2) Colonic motility index and frequency of intraluminal pressure waves showed a significant increase in the IBS group (p<0.01) compared with those of the control group (p<0.001) during MDT stress. (3) Coefficient of variation of RR interval showed a posivive correlation with changing value of colonic motility index (r, =0. 55,p<0.01). (4) Plasma concentration of motilin revealed a significant increase in the IBS group after MDT stress (p<0.01), and the value differed significantly from that of the control group (p<0.05). However, gastrin, glucagon, and substance P in the blood disclosed no significant change. 5) Stress interview caused significant elevation of colonic motility index in the IBS group (p<0.02) as well as MDT Ioading. (6) Administration of neostigmine and propranolol induced a significant increase of colonic motility index in the IBS group, which differed from that in the control group (p<0.01l, p<0.05). On the contrary, no significant difference was observed between IBS and control groups by administration of atropine, isoproterenol and naloxone. (7) According to the reaction under the experimental study, patients with IBS could be classified as follows ; (i ) An obviously stressrelated group whose functional disturbance is caused by psychological stress (psychosomatic disease). (ii) A no or little stressrelated group which has functional disturbance of the bowel constitutionally. (iii) A group which has abdominal complaints without functional disturbance (neurosis). These findings suggest that IBS is heterogenous and that the first group, which can be named as the psychosomatic disease group, revealed reasonable pathogenesis of IBS that hypermotility of intestinal smooth muscle is caused by abnormal excitation of the autonomic (mainly parasympathetic) nervous system, abnormality of some receptors, and/or hypersecretion of gastrointestinal hormones.

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Most of the diseases which are considered psychosomatic are socalled stress Induced diseases ("the diseases of adaptation") and bronchial asthma is one of them. The subjects of the present study consisted of those asthmatic patients who were seen at our psychosomatic department. We gave them the stressors which were assumed to participate in the development of their asthmatic attacks and examined the changes in clinical symptoms, pulmonary function and chemical mediators before and after giving the stresors. The results were summarized as follows : l. In the mirrordrawing test, 5 out of 8 cases showed an increase in plasma histamine and 3 out of them showed an increase in the _cAMP vs _cGMP ratio, but no clear asthmatic attacks appeared. 2. With regard to the listening of recorded wheezing sound, a more than 20% increase in respiratory resistance and an increase in the _cAMP vs _cGMP ratio were seen in 9 out of 16 cases, but no clear asthmatic attacks appeared. 3. In the inhalation test with a suggestion of house dust, 12 out of 23 cases showed a more than 20% decrease in FEV_1._0,but only 5 cases had asthmatic attacks. 4. In the excercise test to induce asthmatic attacks by ascending and descending stairs, 20 out of 29 cases developed asthmatic attacks. Many of these patients showed increases in plasma histamine and cortisol levels. 5. Fortyone asthmatic patients were selected from the inpatients who seemed to have difiiculties in family relationships. They were ordered to stayout at their homes in the early stage of psychosomatic treatment. Thirty-six out of 41 cases developed asthmatic attacks and many of them had a tendency to show some rise in plasma histamine levels prior to going back to their families. 6. These stress-induced asthmatic attacks did not appear in the patients who showed favorable results by psychosomatic treatment. These results indicate that the onset and course of socalled stressinduced diseases ("the diseases of adaptation") are influenced significantly, not only by the patient's predisposition, the kind and intensity of stressors and their duration, but also by the patient's perception of and coping behavior to the stressors and his psychophysiological condition under the stressors. It was keenly felt that psychosomatic treatment was indispensable for so-called stressinduced diseases.

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Psychophysiological analyses of stress by conditioned emotional stimuli were made while Ss watched an inverted T shaped pattern on a CRT display. S_s were told to receive a noxious electric shock at the end of an alternative horizontal period. While spontaneous skin potential responses (SPR) decreased in number during the vertical period, a burst of SPR developed near the end of the horizontal period in a shock anticipation trial. All Ss showed an initial acceleration and followed a deceleration curve in heart rate (HR) during the horizontal period in a shock anticipation period. These results were discussed in relation to. the initial acceleration of sympathetic overactivity (rejection of environment) and secondary acceleration of parasympathetic overactivity (environmental intake) involved in stress. Using the more detail analysis of stress, power spectra of photoelectric finger plethysmogram via Fourier transform were examined. The spectrum below 0.3 H_z was the most prominent at severely variated baseline deflection, and was corresponded to the increasing number of spontaneous SPR and HR under the emotional stress. On the other hand, vertex slow potential change (contingent negative variation, CNV) related to expectancy or attention, and SPR were recorded simultaneously during a constant 2 sec interval between a warning stimulus (pip tone, S_1) and an imperative stimulus (fiash of light, S_2) which they terminated by a motor or mental response (R). When subjects were told to turn off S_2 by a R, both CNV and SPR increased in amplitude. SPR showed diphasic or positive wave dominantly and did not habituate over trials. These results were also interpreted as suggesting the occurrence of stress conditioning during the CNV paradigms. In self obsessivecompulsive state under the repeated stimulation of stress, there was a delay and stability of choice reaction time as compared with rejection of environment and environmental intake. The interpretation of this fact is complex since there exists the possibility of a nonspecific neurofunctional inhibition (improbable as a unique factor), as well as morbid interferences of stress memory and also of adherences to the preceding stimuli (incapacity of commutation) so frequent in an obsessivecompulsive state. These reports support the assumption that bodily responses such as SPR. HR, power spectrum of PTG baseline deflection, CNV, tapping fusion and choice reaction time are likely to be performing a significant role in physiological mechanism correlated with the several stress conditionings.

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