Adult and chronic diseases have been ranked as today's leading diseases. This leads us to develop a psychosomatic pathogenetic model of organic diseases, stressing the importance of psychosocial factors of patients. We tested and discussed how these factors influence organic diesases from experimental and clinical standpoints. Using animal experiments, we showed the changes of the immune system in stress state in the process beginning with stress to the development of organic diseases. We also reported a clinical case of alopecia which showed changes in the ratio of OKT4/0KT8 of T cells by emotional stress. On the other hand, we proved evidence of action of psychosocial factors upon patients before they developed the attack of leading allergic diseases such as chronic urticaria and bronchial asthma. In addition, we studied personal characteristics which were programmed to develop stress state rather easily, as for example, emotional suppression in paticular patients, such as a cancer patient. These increasing factors must be considered very important in the pathogenesis of organic diseases.

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Over the past twenty years, neurochemical research has developed and provided evidences of existances of various substances to act as neurotransmitters or neuromodulators in the brain. We have focused on noradrenaline (NA) out of brain substances and invetigated its involvement in emotional changes (anxiety and/or fear) induced by stress, which is known to elicite various changes in many physiological functions and to be one pathogenic factor of psychosomatic disease. Onehour immobilization stress caused increases in NA release in nine brain regions of rats examined, as indicated by increases in 3-methoxy-4-hydroxyphenylglycol sulfate (MHPGS0_4) levels. Stressinduced increases in NA release were inhibited by diazepam, a typical benzodiazepine (BDZ) anxiolytic, in the hypothalamus, amygdala, hippocampus, cerebral cortex and LC region, but not in other regions. Such blocking effect of diazepam in above brain regions were antagonized by Ro 15-1788,a BDZ receptor antagonist, and by picrotoxin, a GABA antagonist acting on the site of chloride channel coupled with GABA receptors, although picrotoxin did not antagonize diazepam effect only in the amygdala. FG 7142,one of β-carbolines which have been reported to elicite anxiety in human and animals by interacting GABA/BDZ receptor complex, caused NA release similarly to stress in the hypothalamus, amygdala, thalamus, hippocampus and cerebral cortex. Together with these findings, we proposed a hypothesis that stressinduced increases in brain NA release in some brain regions such as the hypothalamus and amygdala, may be related to the provocation 0L anxiety and/or fear and that such NA release may be functionally regulated by GABA/BDZ receptor complex. Not only our data but also other numerous evidences obtained from neurochemical research raise a possibility that various substances including NA in the brain may be involved in many physiological functions 0L the organism, e, g, emotion, autonomic nervous system, immunity, etc. Therefore, neurochemical research of the brain seems to be an important strategy scientifically to reveal the pathogenesis and pathophysiology of psychosomatic diseases.

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Monoamine receptor sensitivity in the central nervous system (CNS) of depressive patients was evaluated by making two drugloading tests and measuring 5HT-induced shape change of blood platelet(5HT-SC. The application of these loading tests and measurement of 5HT-SC to psychosomatic disease was discussed. l) Clonidine is a specific α-2 adrenergic receptor (α-2 receptor) agonist. The presynaptic and postsynaptic a2 receptor sensitivity can be assessed by determining the plasma level of noradrenaline (NA) and human growth hormone (HGH) after an oral loading of clonidine ( 3 μg/kg). Results obtained in depressive patients were as follows : Significantly low decrease rate of plasma NA was found in the depressive patients before treatment and it returned to normal on recovery. The depressive patients with severe symptoms showed a low decrease rate of plasma NA, which elevated within normal level on recovery. The HGH response was blunted in 61.5% of depressive patients before treatment, whose ratio of the blunted response reduced to 23.1% on recovery. These results suggest that the sensitivity of both presynaptic and postsynaptic a2 receptor decreased in depression. 2) In order to know the serotonin (5HT) receptor sensitivity, a precursor loading study with L5hydroxytryptophan (5HTP) was made. Depressive patients were given an intravenous loading dose of 5HTP ester ( 2 mg/kg) after premedication with the peripheral decarboxylase inhibitor, benserazide (60 mg) and were investigated for the subsequent change in mental state and blood parameter (free tryptophan, 5HT, cyclic AMP and GMP, prolactin and HGH). According to the change after 5HTP ester, the depressive patients were devided into two groups, the one of which showed a normal blood level of free tryptophan and 5HT but relatively slight mood elation and psychomotor activity. The results suggest that there may be a blunted sensitivity of 5HT receptor in the CNS of this group. 3) 5HT-SC, the degree of which is thought to refiect the sensitivity of 5HT2 receptor in the CNS, was measured in depressive patients. 5HT-SC in depressive patients was unchanged in untreated depressive state, however, significantly increased in recovery state. The results suggest that antidepressants may increase the functional sensitivity of 5HT-2 receptor in the CNS. 4) As to the application to psychosomatic disease, all of the above-mentioned methods are practical to patients with psychosomatic disease. However, the aggravation of disease by loading test should be avoided unconditionally. The results obtained in depressive patients strongly suggest that these methods are useful for evaluating the monoamine receptor sensitivity in the CNS and for elucidating the cause of psychosomatic disease.

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A great number of research has been directed toward identifying the biological mechanisms of increased risk of coronary heart disease (CHD) among Type A persons. It was often reported that Type A's showed greater cardiovascular responsivity, especially beta-adrenergic, than Type B's during various stressful situations. Recent evidence from our laboratory, however, has suggested a tendency for enhanced alpha-aderenergic and vagal reactivity in Type B individuals. which led to the hypothesis that Type A's and Type B' s might differ in general autonomic balance. In order to test this hypothesis, the present study investigated cardiovascular reactivity of young healthy male Type A (n=11) and Type B (n=13) subjects during mental arithmetic (MA), which, dominantly elicits a betaadrenergic response, and cold face stimulus (CFS), which mainly elicits alphaadrenergic and vagal responses. There was no group difference in response to Ma. However, during CFS, Type B's showed more prolonged decrease in heart rate (p<0.02 : ANOVA) and forearm blood flow (p<0.03) as the increase in systolic blood pressure (p<0.03) and diastolic blood pressure (p<0.03). These findingo suggested that. Type B's exhibited alphaadrenergic and parasympathetic hyperreactivity in contrast with enhanced betaadrenergic responsivity in Type A's. Such differences in autonomic balance might account for the different CHD risk among the people with Type A and Type B behavior patterns.

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