Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology最新文献

Recent research has demonstrated that complex 'epigenetic' mechanisms, which regulate gene transcription without altering the DNA code, could play a critical role in the pathophysiology of psychiatric disorders. We previously reported that pretreatment of mice with 5-HT(1A) receptor agonists 24 hr before testing suppressed the decrease in emotional behaviors induced by exposure to acute restraint stress. In addition, DNA microarray analysis showed that such a pretreatment with 5-HT(1A) receptor agonist produces changes in several gene transcriptions in the hippocampus including the reduction of histone deacetylase 10. Based on these findings, we recently carried out studies focused on the relationship between the development of emotional resistance to stress and histone acetylation induced by a 5-HT(1A) receptor agonist as well as a histone deacetylase inhibitor. The findings suggest that 5-HT(1A) receptor agonists may be useful for preventing mental illnesses that arise due to a decreased resistance and adaptability to stress. Moreover, the notion that chromatin remodeling is an important mechanism in mediating emotionality under stressful situations is further supported.

The incidence of dementia and diabetes mellitus is increasing at an alarming rate, and has become a major public health concern all over the world. Recent epidemiological studies suggest that the risk of Alzheimer's disease is increased in individuals with diabetes mellitus, although the underlying mechanisms remain largely unknown. To analyze underlying mechanisms linking Alzheimer's disease and diabetes mellitus, we established unique animal models that show pathological manifestations of both diseases. Our findings suggest that impaired brain insulin signaling and cerebrovascular changes could be potential underlying mechanisms for this relationship. On the other hand, interestingly, Alzheimer's amyloid pathology aggravated diabetes mellitus in these mouse models, suggesting the presence of mutual interaction between these diseases. In addition, we also found that plasma Abeta levels rapidly and strikingly increased after glucose loading in Alzheimer's disease mouse models, which could be a novel diagnostic marker of Alzheimer's disease. The current review summarizes the results of our recent studies on the pathological relationship between these diseases, which could provide novel insights into this intensely debated association.

Metabolic disorders, such as diabetes and obesity, have been indicated to disturb the function of the central nervous system (CNS) as well as several peripheral organs. Clinically, it is well recognized that the prevalence of anxiety and depression is higher in diabetic and obesity patients than in the general population. We have recently indicated that streptozotocin-induced diabetic and diet-induced obesity mice have enhanced fear memory and higher anxiety-like behavior in several tests such as the conditioned fear, tail-suspension, hole-board and elevated open-platform tests. The changes in fear memory and anxiety-like behavior of diabetic and obese mice are due to the dysfunction of central glutamatergic and monoaminergic systems, which is mediated by the changes of intracellular signaling. These results suggest that metabolic disorders strongly affect the function of the CNS and disturb the higher brain functions. These dysfunctions of the CNS in diabetes and obesity are involved in the increased prevalence of anxiety disorders and depression. Normalization of these dysfunctions in the CNS will be a new attractive target to treat the metabolic disorders and their complications.

The atypical antipsychotic medication olanzapine is a useful agent in acute and maintenance treatment of schizophrenia and related disorders. It has beneficial effects on both positive and negative symptoms, an early onset of antipsychotic action and a favourable side effect profile. On the other hand, olanzapine has many reports of causing weight gain, glucose metabolism disturbances and lipidosis. We carried out blood tests (leptin, adiponectin, remnant-like lipoprotein cholesterol (RLP-C), total cholesterol, HbA1C, 75-OGTT and etc.) on patients with schizophrenia who had taken olanzapine. As a result, leptin, neutral lipid and RLP-C were significantly correlated by BMI. (The average blood test data and BMI revealed a normal range). Most analysis results of the lipoprotein fraction by a polyacrylamide-gel-electrophoresis method were normal patterns. Furthermore, the serum insulin concentrations from 75 g glucose tolerance (75 g-OGTT) 30 minutes later, in one third of patients receiving olanzapine, registered more than 100 microU/ml. The mechanism of the insulin secretion rise by olannzapine is unknown. Olanzapine may impair glucose tolerance due in part to increased insulin resistance. These findings do not necessarily imply that olanzapine is directly associated with a risk of impairment of weight gain, glucose metabolism disturbances and lipidosis. These results suggest that it is useful to promote diet cure and exercise therapy with patients with high BMI levels.

Epigenetic mechanisms typically involve heritable alterations in chromatin structure, which, in turn, regulate gene expression. Fundamental insights about epigenetic heritability have come from studies of cell division and development. However, there is increasing evidence that the regulation of chromatin structure through histone modifications and DNA methylation might mediate the expression of key genes involved in acquired chronic disorders. This idea is fascinating because similar mechanisms are used for triggering and storing long-term memories at the cellular level during, for example, higher-brain dysfunction, stress disease, drug dependence, aging, and chronic pain. This review will explore the most current issues in the field of epigenetics, with a focus on next levels of transcriptional mechanisms underlying aging, enriched environment and drug addiction. Epigenetic mechanisms, which are key cellular and molecular processes that integrate diverse environmental stimuli to exert potent and often long-lasting changes in gene expression through the regulation of chromatin structure, contribute to transcriptional and behavioral changes.

Neurological injuries are widely known to promote neurogenesis in the adult hippocampal dentate gyrus. Our previous studies demonstrated that the granule cells in the hippocampal dentate gyrus are injured and eradicated by treatment with trimethyltin (TMT), with being regenerated in the dentate granule cell layer (GCL) after neuronal loss. Recent collective reports indicate that during brain injury and in neurodegenerative disorders, neurogenesis is controlled by cytokines, chemokines, neurotransmitters, and reactive oxygen/nitrogen species, which are released by dying neurons as well as by activated macrophages, micro-glia, and astrocytes. To elucidate the role of activated microglia in the neuroregeneration following the dentate granule cell loss, in this study, we evaluated the involvement of activated microglial cells and a related factor in the generation of newly-generated cells of the hippocampal dentate gyrus following neuronal loss induced by TMT. Our results support the possibility that pro-inflammatory cytokines released from activated microglial cells may be involved in promotion of the neurogenesis mechanism through activation of the NF-kappaB signaling pathway following the dentate neuronal loss induced by TMT treatment.

The relationship between the polymorphisms (SNPs) of the beta-adrenergic receptor (beta-AR) gene and personality assessed by TCI (Temperament and Character Inventory), was studied among 192 healthy Japanese subjects (121 male subjects and 71 female subjects). In this study, the statistical analyses were performed overall and separately for each sex. As a result, it was shown that there were significant relationships between SD (self-directedness) and 49Ser/Gly (rs1801252) in ADRB1, P (persistence) and 389Arg/Gly (rs1801253) in ADRB1, and ST (self-transcendence) and 27Gln/Glu (rs1042714) in ADRB2 overall. Among the male subjects, there were further significant relationships between ST and 49Ser/Gly in ADRB1, NS (novelty-seeking), HA (harm avoidance) and P and 389Arg/Gly in ADRB1, and P and 64Arg/Trp(rsrs4994) in ADRB3. Among the female subjects, there were also significant relationships between SD and 49Ser/Gly in ADRB1, and C (cooperativeness) and 389Arg/Gly in ADRB1. Thus it was shown that there were correlations between beta-AR gene polymorphisms and several subscales of TCI.

Collegium Internationale Neuropsychopharmacologicum (CINP) is an international society which was established to facilitate academic exchange of basic and clinical studies related to psychotropic drugs. The CINP has been devoted to the problems of methodology and to the analysis of the pharmacological and therapeutic results with psychotropic drugs under normal and pathological conditions as well to the medico-social implications of neuropsychopharmacology. The CINP was organized by Prof. Trabucchi (Milan) in collaboration with an international team of neuropsychopharmacologists from 15 countries. The first International CINP Congress was held on September of 1958 in Rome. Thereafter, CINP world congresses were held every two years until 2012. The number of Japanese neuropsycho-pharmacologists who are members has been increasing since the 1970s. The 17th CINP Congress was held in Kyoto in 1990, and the CINP Hiroshima regional meeting was held, combined the annual meeting of the Japanese Society of Neuropsychopharmacology and Korean Society of Psychopharmacology in 2001. The early history of CINP between 1958 and 2000 is briefly described with special reference to the participation of the Japanese Society of Neuropsychopharmacology.

Depression is a stress-induced disorder and there is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in the disease. Chronic hyperactivity of the HPA axis and resultant excessive glucocorticoid (hypercortisolism) may be causal to depression. We demonstrated that the dexamethasone (DEX)/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities. Restoration from HPA axis abnormalities occurs with clinical responses to treatment. Brain-derived neurotrophic factor (BDNF) has also been implicated in depression. We found that glucocorticoid (DEX) suppresses BDNF-induced dendrite outgrowth and synaptic formation via blocking the MAPK pathway in early-developing cultured hippocampal neurons. Furthermore, we demonstrated that glucocorticoid receptor (GR) and TrkB (a specific receptor of BDNF) interact and that DEX acutely suppresses BDNF-induced glutamate release by affecting the PLC-gamma pathway in cultured cortical neurons, indicating a mechanism underlying the effect of excessive glucocorticoid on BDNF function and resultant damage in cortical neurons. In a macroscopic view using magnetic resonance imaging (MRI), we found that individuals with hypercortisolism detected by the DEX/CRH test demonstrated volume loss in gray matter and reduced neural network assessed with diffusion tensor imaging in several brain regions. Finally, we observed that individuals with hypocortisolism detected by the DEX/CRH test tend to present more distress symptoms, maladaptive coping styles, and schizotypal personality traits than their counterparts, which points to the important role of hypocortisolism as well as hypercortisolism in depression spectrum disorders.

The important functional role of fatty acids in both onset and suppression of pain has become increasingly apparent in recent years. Recently, we have also demonstrated that the release of an endogenous opioid peptide, beta-endorphin, plays an important role in the induction of docosahexaenoic acid (DHA)-induced antinociception. It is well known that fatty acids affect intracellular and intercellular signaling as well as the membrane fluidity of neurons. In addition to intracellular actions, unbound free fatty acids (FFAs) can also carry out extracellular signaling by stimulating the G-protein-coupled receptor (GPCR). Among these receptors, GPR40 has been reported to be activated by long-chain fatty acids such as DHA, eicosapentaenoic acid (EPA) and arachidonic acid. In a peripheral area, GPR40 is preferentially expressed in pancreatic beta-cells and is known to be related to the secretion of hormone and peptides. On the other hand, even though this receptor is widely distributed in the central nervous system, reports studying the role and functions of GPR40 in the brain are not found. In this review, we summarize the findings of our recent study about the long-chain fatty acid receptor GPR40 as a novel pain regulatory system.