Tatsuo Mita

Decreased Serotonin S2 and Increased Dopamine D2 Receptors in Chronic Schizophrenics

Serotonin S2 and dopamine D2 receptors in the prefrontal cortex and caudate nucleus of postmortem brains of chronic schizophrenics were studied using 3H-ketanserin and 3H-spiperone, respectively. In the prefrontal cortex of schizophrenics, we found a significant decrease in the maximum number of 3H-ketanserin binding sites (Bmax), with no change in the dissociation constant (Kd). Conversely, both Bmax and Kd of 3H-spiperone binding to the caudate nucleus were significantly increased in the schizophrenic patients. There were no differences in receptor indices between patients who were taking neuroleptics until their death and those who had taken none for 2 months or more prior to death. These findings suggest that alterations in S2 receptors in the prefrontal cortex may reflect the disease process, per se, and that the increase in the number of D2 receptors in the caudate nucleus of schizophrenics is not due solely to neuroleptic medication.

[3H]Muscimol binding sites increased in autopsied brains of chronic schizophrenics

[3H]muscimol binding and glutamic acid decarboxylase (GAD) activity in the prefrontal cortex and caudate nucleus of autopsied brains from 19 chronic schizophrenics and 17 control subjects were investigated. In the schizophrenics, saturation analysis with varying concentrations of [3H]muscimol revealed an increase in the number of GABAA receptors, but there was no significant difference in the affinity. In addition, the enhancement of [3H]muscimol binding by diazepam was significantly greater in schizophrenics than in controls. GAD activity did not differ between controls and schizophrenics. The possibility that GABAergic mechanisms might play a role in case of chronic schizophrenia should be given further attention.

Differential changes in serotonin 5-HT1A and 5-HT2 receptor binding in patients with chronic schizophrenia.

Serotonin 5-HT1A and 5-HT2 receptors were examined in the postmortem brains of controls and patients with chronic schizophrenia. In the prefrontal cortex from patients with schizophrenia, 5-HT1A receptor binding was increased, while 5-HT2 receptor binding was decreased, when compared to controls. The increased 5-HT1A receptor binding or the decreased 5-HT2 receptor binding was observed in both the patients who had been medicated with neuroleptics at time of death and those who had not, at least 2 months prior to death. Thus, abnormalities of 5-HT receptor subtypes seem to exist in the brains of patients with chronic schizophrenia. 5-HT related agents might be beneficial for the treatment of schizophrenia.

Decreased histamine H1 receptors in the frontal cortex of brains from patients with chronic schizophrenia

Involvement of histamine H1 receptor in the brains of schizophrenic patients was investigated using 3H-mepyramine as a ligand. The specific 3H-mepyramine binding in the frontal cortex was saturable with the dissociation constant (Kd) of about 0.6 nM and the maximum number of binding sites (Bmax) of 64 fmol/mg protein. Specific H1 antagonists, mepyramine (Ki = 1.4 nM), promethazine (Ki = 1.4 nM), diphenylpyraline (Ki = 4.1 nM), triprolidine (Ki = 5.3 nM), diphenylhydramine (Ki = 35 nM), but not the specific H2 antagonist, cimetidine (Ki greater than 10(5) nM), strongly inhibited the 3H-mepyramine binding. Regional distribution of the specific 3H-mepyramine binding was in the order of: frontal cortex greater than hippocampus greater than cerebellum greater than hypothalamus greater than thalamus, putamen, and pallidum. The specific 3H-mepyramine binding in schizophrenic brains was reduced by 56% in the frontal cortex. Representative Scatchard analyses of the specific 3H-mepyramine binding revealed changes resulting from a decrease in receptor density but not in receptor affinity. Down-regulation of the histamine H1 receptor in the frontal cortex may be involved in the pathophysiology of schizophrenia.

Increase in [3H]cAMP binding sites and decrease in Giα and Goα immunoreactivities in left temporal cortices from patients with schizophrenia

To search for possible alterations in second messenger systems in the temporal cortex (Brodmans area 22) of patients with schizophrenia, we measured the binding activities of [3H]adenosine 3′,5′-cyclic monophosphate ([3H]cAMP) and [3H]4β-phorbol 12,13-dibuytrate ([3H]PDBu) which can label the regulatory subunit of cAMP-dependent protein kinase (protein kinase A) and the regulatory domain of Ca2+/phospholipid-dependent protein kinase (protein kinase C), respectively. We also immunoquantified the variable subunits of guanine nucleotide binding proteins (G-proteins), using specific polyclonal antisera against Gsα, Giα and Goα. Brains were obtained at autopsy on 10 patients with schizophrenia and 10 age-matched control subjects. Representative Scatchard plots for specific [3H]cAMP bindings to the soluble fraction consisted of a single component with high affinity (Kd = 2.36 nM, Bmax = 737fmol/mg protein. Among the tested adenyl and and guanyl nucleotides, or neuroleptics, cAMP alone potently inhibited the binding (Ki = 4.95 nM). The binding sites for [3H]cAMP were discretely localized, and were in the order of: cerebral cortex = hypothalamus= amygdala > hippocampus = neostriatum = thalamus = nucleus accumbens > globus pallidus = cerebellum. Specific [3H]cAMP binding to the soluble fractions were about 30% greater in the left temporal cortices of schizophrenic patients, as compared to findings in the right side of the patients and the left side of the control subjects, no control brain showed this asymmetry. The specific [3H]PDBu binding in schizophrenic and control groups did not change. Giα and Goα immunoreactivities in the crude membranes were decreased by about 30% in the left temporal cortices of schizophrenic patients, as compared to findings in the controls, on the left side, while Gsα immunoreactivities were unchanged between the two groups, on either side. Our findings suggest the enhanced responsiveness of adenylate cyclase to receptor stimulation through relative preponderance of Gsα over Giα, which in turn would facilitate the generation of regulatory subunits of protein kinase A. The significance of decreased Goα immunoreactivities in schizophrenia is the subject of ongoing study. Our observations support the hypothesis of left (‘dominant’) temporal lobe dysfunction in schizophrenia.

Factors associated with motivation and hesitation to work among health professionals during a public crisis: a cross sectional study of hospital workers in Japan during the pandemic (H1N1) 2009

BackgroundThe professionalism of hospital workers in Japan was challenged by the pandemic (H1N1) 2009. To maintain hospital function under critical situations such as a pandemic, it is important to understand the factors that increase and decrease the willingness to work. Previous hospital-based studies have examined this question using hypothetical events, but so far it has not been examined in an actual pandemic. Here, we surveyed the factors that influenced the motivation and hesitation of hospital workers to work in Japan soon after the pandemic (H1N1) 2009.MethodsSelf-administered anonymous questionnaires about demographic character and stress factors were distributed to all 3635 employees at three core hospitals in Kobe city, Japan and were collected from June to July, 2009, about one month after the pandemic (H1N1) in Japan.ResultsOf a total of 3635 questionnaires distributed, 1693 (46.7%) valid questionnaires were received. 28.4% (N = 481) of workers had strong motivation and 14.7% (N = 249) had strong hesitation to work. Demographic characters and stress-related questions were categorised into four types according to the odds ratios (OR) of motivation and hesitation to work: some factors increased motivation and lowered hesitation; others increased motivation only; others increased hesitation only and others increased both motivation and hesitation. The strong feeling of being supported by the national and local governments (Multivariate OR: motivation; 3.5; CI 2.2-5.4, hesitation; 0.2; CI 0.1-0.6) and being protected by hospital (Multivariate OR: motivation; 2.8; CI 2.2-3.7, hesitation; 0.5; CI 0.3-0.7) were related to higher motivation and lower hesitation. Here, protection included taking precautions to prevent illness among workers and their families, providing for the care of those who do become ill, reducing malpractice threats, and financial support for families of workers who die on duty. But 94.1% of the respondents answered protection by the national and local government was weak and 79.7% answered protection by the hospital was weak.ConclusionsSome factors have conflicting effects because they increase both motivation and hesitation. Giving workers the feeling that they are being protected by the national and local government and hospital is especially valuable because it increases their motivation and lowers their hesitation to work.

Change of suicidal ideation induced by suicide attempt

Abstract  Some studies have reported that a suicide attempt has a cathartic effect. We studied a change of suicidal ideation just before and after a suicide attempt to test whether a cathartic effect exists and, if a cathartic effect does exist, to identify factors that may affect it. Subjects consisted of 88 suicide attempters (29 males, 59 females, mean age = 35.5 years) who attended the emergency medical center of Kobe City General Hospital, Kobe, Japan. Strength of suicidal ideation just before and after a suicide attempt was evaluated by 11 steps from 0 to 10, where 0 indicates no suicidal ideation and 10 indicates the strongest suicidal ideation. Subjects were also interviewed about any clinical backgrounds related to suicide attempts. Diagnoses were made by psychiatrists based on ICD‐10. Scores of suicidal ideation decreased significantly after the suicide attempt in comparison with those just before the suicide attempt (P < 0.0001). In suicide attempters of each generation under 60 years of age, there were significant decreases in scores of suicidal ideation after the suicide attempt, but not in those of over 60 years of age. Scores of suicidal ideation after the suicide attempt were significantly higher in the group of F4 classified by ICD‐10 than that of F2. Our results indicate that the cathartic effect induced by suicide attempt is different among generations and psychiatric disorders.

Asymmetrical changes in the fodrin α subunit in the superior temporal cortices in schizophrenia

Background: We examined possible abnormalities in neural structural proteins that may underlie morphometric changes reported in the left superior temporal cortices (Brodmanns area 22) of schizophrenics. Methods: Particulate proteins of the superior temporal cortices taken at autopsy from 11 schizophrenic and 9 control brains were fractionated by gel electrophoresis. Target proteins, identified by reading their amino acid sequences, were immunoquantified using the specific antibody. Results: Amino acid sequences of the 150-kDa proteins on sodium dodecyl sulfate/polyacrylamide gel electrophoresis, which were significantly increased on the left side of schizophrenic superior temporal cortices, revealed that they were proteolytic fragments of the α subunit of fodrin, a major cytoskeletal protein underlying the plasma membrane. Immunoquantification using the specific antibodies against α and β subunits of fodrin indicated that there exist concomitant decreases in the full-length 240-kDa form and increases in the 150-kDa, form of α fodrin with no changes of the 235-kDa form of β-fodrin in the left superior temporal cortices of the schizophrenic brains. Conclusions: The findings may be a possible molecular basis for linking morphometric changes to neurochemical pathophysiology in schizophrenia.

Psychological impact of the pandemic (H1N1) 2009 on general hospital workers in Kobe.

Aims:  In order for hospitals to work efficiently in a pandemic, it is important to know how a pandemic affects the hospital staff. The aim of the present study was to investigate the psychological impact of the pandemic (H1N1) 2009 on hospital workers and how it was affected by the characteristics of the hospital, gender, age, job and work environment.

Isolated adrenocorticotropic hormone deficiency accompanied with delirium

MANY STUDIES HAVE indicated an intact phonological loop (PL) as a subsystem of working memory (WM) in people with schizophrenia (PWS). Some WM tasks are more dependent on the PL than others, such as serial recall tasks. However, using a word serial recall test and a tone delay discrimination test, Bruce et al. showed one subgroup of PWS with a selective deficit in verbal memory. It is suggested that semantic long-term memory has an active role in the recall of short-term memory. There is a difference in semantic demand of verbal tasks such as forward digit span and nonverbal tasks, like the tone delay task. So it is assumed that the semantic aspect of mentioned tasks may play an important role in identifying any potential PL deficit. The nonword repetition task (NRT) has been used in various studies to examine the PL in children with specific language impairment and other language impairments. To investigate PL by NRT, we enrolled nine chronic male PWS [mean age = 34.3y, standard deviation (SD) = 9.15] and ten ageand educationally-matched healthy men (mean age = 35.11, SD = 8.60). No speech or hearing impairment was reported in their recordings. All PWS were taking atypical antipsychotics for at least 6 months. Sixty-nine phonotactically similar monosyllabic nonwords in Azerbaijani language were used as task stimuli. Using the Mann–Whitney test, a significant difference was found for the nonword repetition error numbers between both groups (P = 0.001). The PWS made more errors in repetition of the nonwords (mean = 48.88, SD = 13.57) than normal participants (mean = 19, SD = 11.01). This finding is contrary to previous studies that used forward digit span tasks that indicated intact PL in PWS. But it is consistent with the findings of Wexler et al. and Stevens et al., which have shown dysfunctions in the left inferior frontal cortex in PWS who have specific performance deficits in verbal but not nonverbal WM. The NRT without semantic load revealed the deficits of PL in PWS. As Green et al. have shown improvement of verbal WM and other cognitive functions in PWS who use risperidone, we suggest that further analysis of the effect of the drugs on the deficit is needed.