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

The axon initial segment (AIS) is a highly specialized neuronal subregion that separates axonal and somatodendritic compartments. The AIS is enriched with voltage-gated Na+ channels, and plays a critical role in determining neuronal activity. Recently, our understanding of AIS has seen major advances. Types and density of ion channels within the AIS vary among different neuronal types, which may underlie the variations in firing of neurons in the brain. Distribution of the AIS itself is not uniform among neurons either; rather, it is delicately determined in each neuron to meet its specific need. Furthermore, the AIS has a capacity for plasticity and reorganizes its distribution to regulate neural activity. In this review, I will show how these newly found features of AIS contribute to shape the function of neural circuits that are involved in the integration of binaural timing information for sound localization in birds.

Higher impulsivity could be a risk factor for drug addiction, criminal involvement, and suicide. Moreover, poor inhibitory control is observed in several psychiatric disorders such as attention-deficit/hyperactivity disorder, schizophrenia, and bipolar disorder. Thus it is preferred that clinical drugs have anti-impulsive effects in addition to the therapeutic effects on the primary disease. At least it is better to use clinical drugs that do not increase impulsivity. We have developed a 3-choice serial reaction time task and examined the effects of clinical drugs on impulsivity in rats using the task. We have found several anti-impulsive drugs (lithium, tandospirone, and milnacipran) and elucidated the mechanism of action in some of these drugs. For example, we demonstrated that milnacipran enhanced the control of impulsive action by activating D1-like receptors in the infralimbic cortex. In this review, we introduce recent advances in this field and suggest future directions to develop anti-impulsive drugs.

While the etiology of schizophrenia remains unclear, there has been a growing amount of evidence pointing to neuroinflammation, which is characterized by an increased serum concentration of several pro-inflammatory cytokines and an increase of microglia in the brain of schizophrenics. Microglia respond rapidly to even minor pathological changes in the brain and may contribute directly to neuronal degeneration by producing various pro-inflammatory cytokines and free radicals. In many aspects, the neuropathology of schizophrenia has recently been reported to be closely associated with microglial activation. Our "Microglia Hypothesis of Schizophrenia" may shed a new light on the therapeutic strategy for schizophrenia.

Apolipoprotein E (Apo-E) is a major cholesterol carrier regulating lipid transport and injury repair in the brain. It is known that individuals carrying the epsilon4 allele are at increased risk of Alzheimer disease (AD) compared with those carrying the more common epsilon3 allele, whereas the epsilon2 allele decreases risk. ApoE-HDL binds to several cell-surface receptors to deliver lipids, and also to amyloid-beta (Abeta) proteins. Abeta is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. It has been shown that Apo-E isoforms differentially regulate Abeta aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, and mitochondrial function. In this review, we summarize current knowledge about Apo-E in the CNS, with a particular emphasis on its functions to generate HDL and clear/degradate of HDL-bound Abeta with different ApoE isoforms.

Autism is a neurodevelopmental disorder characterized by impairments in social interaction, communication, and restricted and repetitive behavior. Synaptic defects have been implicated in autism; nevertheless, the cause is still largely unknown. A mutation that substitutes cysteine for arginine at residue 451 of Neuroligin-3 (R451C) is the first monogenic mutation identified in idiopathic autism patients. To study the relationship between this mutation and autism, we generated knock-in mice that recapitulated this mutation. The knock-in mice were born and grew up normally without showing any major physical phenotypes, but showed a deficit in social interaction. We studied synaptic function in the layer II/III pyramidal neurons in the somatosensory cortex and found inhibitory synaptic transmission was enhanced in the knock-in mice. The administration of GABA blocker rescued social interaction, suggesting that this caused autistic behavior in these mice. We also found, by Morris water maze test, that spatial learning and memory were significantly enhanced in the knock-in mice. Electrophysiology in the CA1 region of the hippocampus revealed that LTP, the NMDA/AMPA ratio, and NR2B function were enhanced, indicating that synaptic maturation was impaired in the knock-in mice. This may cause the deficit in social behavior and extraordinary memory ability occasionally seen in autistic patients.

Nicotine produces core symptoms of substance dependence (craving and withdrawal) without any psychotic symptoms. The psychopharmacological structure of craving is hypothesized to be constituted by three components: the primary reinforcing property of a substance, the secondary reinforcing property of that substance (conditioned aspects of the environment, such as contextual or specific cues associated with substance taking), and the negative affective motivational property during withdrawal (i.e. the desire to avoid the dysphoric withdrawal symptoms elicits craving). Among the three components, the primary reinforcing property of a substance forms the most fundamental factor for establishing substance dependence. Sensitization or reverse tolerance observed in locomotor activity of animals, which had been believed to be a methamphetamine psychosis model, is demonstrated to reflect the establishment of conditioned reinforcement. Finally, non-substance-related addiction such as gambling, internet, and sex is discussed. From the aspect of the above hypothetical psychopharmacological structure of craving, the most significant difference between substance dependence and non-substance-related addiction is that the primary reinforcing property of non-substance reward is relatively intangible in comparison with that of a substance of abuse.

In this study, the relationship between the haplotypes consisting of single nucleotide polymorphisms (SNPs) of serotonin 2A receptor (5HT2AR) gene (HTR2A) 102T/C (rs6313) and -1438A/G (rs6311) and smoking behavior was studied among 101 smokers and 99 non-smokers. It was shown that the genotypic and allelic frequencies of these polymorphisms were not associated with the smoking behavior. However, according to haplotype analysis, higher haplotype 1 ((-1438G) G-(102)T) frequency was observed in smokers than in non-smokers (P < 0.05). Pairwise D' and gamma2 values between the two SNPs in this study were 0.916 and 0.805, respectively. The two SNPs thus showed strong linkage disequilibrium with each other. This study suggests that 5-HT2AR gene haplotype (G-T) may be related to smoking behavior.

Microglia are generally believed to be brain macrophages, which become phagocytic cells after cellular activation in response to inflammation or injury in the brain. However, accumulating evidence suggests that microglia modulate neurotransmission and synaptic plasticity by secretion of several soluble factors. Importantly, microglia secret glycine to enhance NMDA receptor-mediated responses and hippocampal long-term potentiation, a cellular basis of learning and memory. Although the expression of NMDA receptors was also observed in microglia, NMDA receptor-mediated responses were not induced in microglia. This suggests that NMDA receptors expressed in microglia are not functional. Besides the modulation of synaptic transmission, microglia also play an important role in synaptic remodeling by the pruning of unnecessary synapses and axon terminals during the postnatal developmental stage and adaptation to novel environments even in the healthy brain. Furthermore, we have recently found that clock genes in microglia drive P2Y12R and cathepsin S to regulate diurnal change in the synaptic activity. Therefore, defects in these microglial functions may eventually result in several brain diseases including neuropsychiatric disorders.

N-Methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels with crucial roles in synaptic transmission and central nervous system plasticity. Systemic lupus erythematosus (SLE) is a multi-system inflammatory disorder characterized by the presence of autoantibodies directed against double-stranded (ds) DNA. The pathophysiology of neuropsychiatric (NP) SLE is diverse and complicated. In SLE, anti-dsDNA antibody (Ab) cross-reacts with NMDA receptors. Serum anti-NMDA receptor Ab was found in 30% of SLE patients. We demonstrated the relationship between anti-NMDA receptor Ab and each organ's involvement in SLE, and the biological function of anti-NMDA receptor Ab. The frequency of NP-SLE was significantly higher in the anti-NMDA receptor Ab positive subset than the negative subset, although the frequencies of serositis and nephritis were not significant. Anti-NMDA receptor Ab titer inversely correlated with leukocyte counts and hemoglobin levels. Moreover, regarding to the effects of anti-NMDA receptor Ab on NMDA receptor-transfected cell viability and intracellular Ca2+ level, there was a significant inverse correlation between anti-NMDA receptor Ab titer and cell viability, and a significant association between anti-NMDA receptor Ab titer and intracellular Ca2+ level. In conclusion, anti-NMDA receptor Ab is associated with NP-SLE and cytopenia. Anti-NMDA receptor Ab could cause the injury of NMDA receptor-expressed cells by increasing Ca2+ influx.

Impairment of neuronal plasticity is important in the pathophysiology of mood disorder. Both zinc deficiency and social isolation impair neuronal plasticity. Both cause a depressive state. However, in experiments using animals, their combined loading induced manic-like behavior. Therefore, it was inferred that moderate impairment of neuronal plasticity induces a depressive state, and that further impairment of neuronal plasticity induces a manic state. However, some kind of load toward neuronal function through neural transmission can influence mood disorder symptoms without direct effects on neuronal plasticity. Our hypothesis is that mania is an aggravation of depression from the perspective of neuronal plasticity, and that multiaxial evaluation by neuronal plasticity and neuronal load through neural transmission is useful for understanding the pathophysiology of mood disorder. There are many clinical aspects that have been difficult to interpret in mood disorder: Why is a mood stabilizer or electric convulsive therapy useful for both mania and depression? What is the pathophysiology of the mixed state? Why does manic switching by an antidepressant occur or not? Our hypothesis is useful to understand these aspects, and using this hypothesis, it is expected that the pathophysiology of mood disorder and clinical mechanism of mood stabilizers and antidepressants can now be understood as an integrated story.