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

The abuse of methamphetamine causes abnormal behaviors which are indistinguishable from schizophrenia in humans. Recent reports have shown that selective serotonin reuptake inhibitors (SSRIs) have beneficial effects on methamphetamine-related behaviors, including behavioral sensitization and rewarding effects in animals. However, the exact mechanisms by which SSRIs affect methamphetamine-related behaviors are not yet clear. The present study was designed to investigate the effects of SSRIs on the development of methamphetamine-induced behavioral sensitization and rewarding effects in mice. Behavioral sensitization was measured by examining the locomotor activity of mice in a tilting cage after repeated injections of methamphetamine. Repeated administration of methamphetamine significantly induced a behavioral sensitization. Some SSRIs (fluoxetine and fluvoxamine), which have sigma-1 receptor agonistic activity, inhibited the development of methamphetamine-induced behavioral sensitization. Fluoxetine also dose-dependently attenuated the rewarding effects of methamphetamine as measured by the conditioned place preference paradigm. Furthermore, the sigma-1 receptor antagonist NE-100 significantly reversed the inhibitory effects of fluoxetine on methamphetamine-induced behavioral sensitization and rewarding effects. These results suggest that sigma-1 receptor agonistic activity might be involved in the attenuating effects of fluoxetine and fluvoxamine on methamphetamine-induced behavioral sensitization and rewarding effects.

Our research of stem cell transplantation using mouse embryonic stem (ES) cells and induced pluripotent (iPS) cells was carried out from the aspect of trophic factor, cell differentiation, and better survival of grafted cells. Pleiotrophin, an enhanced trophic factor in the dopamine (DA)-depleted striatum, increased the number of DAergic neurons from ES-derived neural stem cells (ES-NSCs), increased cell survival of cultured DAergic neurons, and affected cell survival of grafted DAergic cells in Parkinson model rats. It was shown that DAergic differentiation from ES-NSCs was mediated by hypoxia inducible factor 1-alpha. Our challenges of the transplantation of ES-NSCs and iPS-derived oligodendrocyte progenitor cells (iPS-OPCs) into periventricular leukomalasia (PVL) model rats are also presented. It was found that grafted ES-NSCs survived better in the corpus callosum without immunosuppressant and most of them differentiated into neurons near the grafted site. It was also revealed that only a few of the grafted iPS-OPCs induced by a stepwise culture method with no use of serum could survive in PVL model rats, indicating that trophic factor (s) and improvement of graft techniques will be needed for better survival of grafted iPS-OPCs.

This review addresses the morphological changes seen in motor neurons and the surrounding non-neuronal cells in the process of regeneration after nerve injury. In addition, the molecular basis for the morphological changes and the gene expression regulation are also addressed. In the CNS, morphological changes of astrocyte and microglia are seen in response to nerve injury, which could be important for neuron survival. In the periphery Schwann cells, macrophages and endoneurial fibroblasts play crucial roles in proper nerve regeneration. For those cellular functions and behaviors, a significant number of mediators among those cells is expressed. In addition to thase intercellular signalings, the intracellular signaling in injured motor neurons is also crucial. In the injured motor neurons, their fate appears to be determined by a balance of the protection and death signals. To properly control expression of those signals, some regeneration-specific transcription factor complexes as well as the epigenetic regulators are emerging.

The author reviews recent findings of a series of experimental studies on snake detection in visual search which he himself has undertaken. It reveals that this method is quite useful as an experimental paradigm to investigate anxiety levels of humans whether they are adults or children.

Social cognition is defined as the capacity to engage in information processing with the aim of accurate cognition of other persons' character or intentions. Development of social cognition can be observed in behavioral patterns. However, their neural basis remains largely unknown. A functional neuroimaging technique has enabled us to observe neural activities in the human brain noninvasively. First the principle and history of functional magnetic resonance imaging (fMRI), and its future perspective are introduced. As an example, presented is our attempt to apply simultaneous fMRI measurements of two individuals to elucidate the neural basis of joint attention, one of the most important behavioral milestones in the development of social cognition. Second, neural substrates of pro-social behavior are discussed. Specifically, it was found that social acceptance or praise is important for human altruistic behavior, and has a neural basis similar to that of basic reward or monetary reward. Lastly, I stress the importance of combining current and ongoing progress in neuroscience, from the 'micro' through 'macro' levels, with scholarship within the humanities. As a connecting node for the different research fields, functional neuroimaging techniques will play a critical for the ultimate goal of comprehensive understanding of human social cognition.

Alpha-synuclein (SNCA) gene expression is an important factor in the pathogenesis of Parkinson's disease (PD). Gene multiplication can cause inherited PD, and promoter polymorphisms that increase SNCA expression are associated with sporadic PD. CpG methylation in the promoter region may also influence SNCA expression. By using cultured cells, we identified a region of the SNCA CpG island in which the methylation status altered along with increased SNCA expression. Postmortem brain analysis revealed regional non-specific methylation differences in this CpG region in the anterior cingulate and putamen among controls and PD; however, in the substantia nigra of PD, methylation was significantly decreased. This CpG region may function as an intronic regulatory element for the SNCA gene. Our findings suggest that a novel epigenetic regulatory mechanism controlling SNCA expression influences PD pathogenesis.

Although mammalian neurogenesis is mostly completed by the perinatal period, new neurons are continuously generated throughout adulthood in the restricted regions of the brain. Newly generated neurons are incorporated into the neural networks of both the hippocampal dentate gyrus and the olfactory bulb, and there is growing evidence that adult neurogenesis is important for various brain functions. Continuous neurogenesis is achieved by the coordinated proliferation and differentiation of adult neural stem cells. In this review, we discuss the recent findings concerning the roles of Notch signaling and Hes-family genes in adult neural stem cells. We also discuss the recent findings about the integration mode of new neurons into the existing neural circuits and the potential significance of adult neurogenesis in higher brain functions, such as spatial and olfactory memory.

Obesity is the most critical factor in the pathology of metabolic syndrome (MetS), and is associated with an increased risk of depression. The imbalance of hormones and neural peptides which are involved in energy regulation are observed in obesity. It becomes evident that these hormones and neural peptides also affect mood. Leptin plays a pivotal role in energy regulation mainly acting in the hypothalamus of the brain. Although obese humans and rodents usually have high circulating levels of leptin, leptin neither reduces food intake nor increases energy expenditure. This paradoxical situation in obesity has been termed "leptin resistance", which is considered to be a central dogma for obesity. Based on these observations, we examined the functional significance of leptin in the regulation of the depressive state in diet-induced obese (DIO) mice. Our recent study demonstrated that DIO mice showed severe depressive behavior without response to the antidepressant effect of leptin, which is, in part, due to the impairment of leptin action in the hippocampus (Yamada, et al., Endocrinology, 2011). MetS and CNS dysfunction might have common pathological bases vulnerable to these disorders. Our future direction is to investigate a new treatment strategy of MetS by analyzing CNS dysfunction associated with obesity.

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. About 10% of all ALS cases are familial; approximately 20% of familial ALS cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene. We developed rats that express a human SOD1 transgene with ALS-associated mutations, developing striking motor neuron degeneration and paralysis. The larger size of this rat model as compared with the ALS mice, will facilitate studies involving manipulations of spinal fluid and the spinal cord. Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. We administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to the transgenic rats at the onset of paralysis for 4 weeks. Intrathecal administration of hrHGF attenuated motor neuron degeneration and prolonged the duration of the disease by 63%. To translate this strategy to human treatment, we induced a contusive cervical spinal cord injury in the common marmoset, a primate, and then administered hrHGF intrathecally. The intrathecal administration of hrHGF promoted functional recovery. These results prompted further clinical trials in ALS using continuous intrathecal administration of hrHGF.