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Impairment in verbal communication abilities has been reported in autism spectrum disorder (ASD). Dysfunction of the serotonergic system has also been reported in ASD. However, it is still unknown how the brain serotonergic system relates to impairment in verbal communication abilities in individuals with ASD. In the present study, we investigated the correlation between brain serotonergic condition and brain sensitivity to paralinguistic stimuli (i.e., amplitude in the human voice prosodic change-evoked mismatch field) measured by magnetoencephalography (MEG) or verbal ability in 10 adults with ASD. To estimate the brain serotonergic condition, we measured the serotonin transporter nondisplaceable binding potential cerebrum-wide using positron emission tomography with [11C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ([11C] DASB). The results demonstrated a significant positive correlation between brain activity to paralinguistic stimuli and brain serotonin transporter binding potential in the left lingual gyrus, left fusiform gyrus and left calcarine cortex. In addition, there were significant positive correlations between verbal ability and serotonergic condition in the right anterior insula, right putamen and right central operculum. These results suggested that the occipital cortex is implicated in recognition of the prosodic change in ASD, whereas the right insula-involved serotonergic system is important in nurturing verbal function in ASD.Trial registration: UMIN000011077.

Visuospatial working memory (WM), which is impaired in schizophrenia, depends on a distributed network including visual, posterior parietal, and dorsolateral prefrontal cortical regions. Within each region, information processing is differentially regulated by subsets of γ-aminobutyric acid (GABA) neurons that express parvalbumin (PV), somatostatin (SST), or vasoactive intestinal peptide (VIP). In schizophrenia, WM impairments have been associated with alterations of PV and SST neurons in the dorsolateral prefrontal cortex. Here, we quantified transcripts selectively expressed in GABA neuron subsets across four cortical regions in the WM network from comparison and schizophrenia subjects. In comparison subjects, PV mRNA levels declined and SST mRNA levels increased from posterior to anterior regions, whereas VIP mRNA levels were comparable across regions except for the primary visual cortex (V1). In schizophrenia subjects, each transcript in PV and SST neurons exhibited similar alterations across all regions, whereas transcripts in VIP neurons were unaltered in any region except for V1. These findings suggest that the contribution of each GABA neuron subset to inhibitory regulation of local circuitry normally differs across cortical regions of the visuospatial WM network and that in schizophrenia alterations of PV and SST neurons are a shared feature across these regions, whereas VIP neurons are affected only in V1., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Social recognition is the sensitive domains of complex behavior critical for identification, interpretation and storage of socially meaningful information. Social recognition develops throughout childhood and adolescent, and is affected in a wide variety of psychiatric disorders. Recently, new data appeared on the molecular mechanisms of these processes, particularly, the excitatory-inhibitory (E/I) ratio which is modified during development, and then E/I balance is established in the adult brain. While E/I imbalance has been proposed as a mechanism for schizophrenia, it also seems to be the common mechanism in autism spectrum disorder (ASD). In addition, there is a strong suggestion that the oxytocinergic system is related to GABA-mediated E/I control in the context of brain socialization. In this review, we attempt to summarize the underpinning molecular mechanisms of E/I balance and its imbalance, and related biomarkers in the brain in healthiness and pathology. In addition, because there are increasing interest on oxytocin in the social neuroscience field, we will pay intensive attention to the role of oxytocin in maintaining E/I balance from the viewpoint of its effects on improving social impairment in psychiatric diseases, especially in ASD., (Copyright © 2018. Published by Elsevier Ltd.)

Objective: Altered brain connectivity has been theorized as a key neural underpinning of autism spectrum disorder (ASD), but recent investigations have revealed conflicting patterns of connectivity, particularly hyper-connectivity and hypo-connectivity across age groups. The application of graph theory to neuroimaging data has become an effective approach for characterizing topographical patterns of large-scale functional networks. We used a graph approach to investigate alteration of functional networks in childhood ASD., Method: Magnetoencephalographic signals were quantified using graph-theoretic metrics with a phase lag index (PLI) for specific bands in 24 children with autism spectrum disorder and 24 typically developing controls., Results: No significant group difference of PLI was found. Regarding topological organization, enhanced and reduced small-worldness, representing the efficiency of information processing, were observed respectively in ASD children, particularly in the gamma band and delta band., Conclusions: Analyses revealed frequency-dependent atypical neural network topologies in ASD children., Significance: Our findings underscore the recently proposed atypical neural network theory of ASD during childhood. Graph theory with PLI applied to magnetoencephalographic signals might be a useful approach for characterizing the frequency-specific neurophysiological bases of ASD., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

The P1m component of the auditory evoked magnetic field is the earliest cortical response associated with language acquisition. However, the growth curve of the P1m component is unknown in both typically developing (TD) and atypically developing children. The aim of this study is to clarify the developmental pattern of this component when evoked by binaural human voice stimulation using child-customized magnetoencephalography. A total of 35 young TD children (32-121 months of age) and 35 children with autism spectrum disorder (ASD) (38-111 months of age) participated in this study. This is the first report to demonstrate an inverted U-shaped growth curve for the P1m dipole intensity in the left hemisphere in TD children. In addition, our results revealed a more diversified age-related distribution of auditory brain responses in 3- to 9-year-old children with ASD. These results demonstrate the diversified growth curve of the P1m component in ASD during young childhood, which is a crucial period for first language acquisition. Autism Res 2016, 9: 1216-1226. © 2016 International Society for Autism Research, Wiley Periodicals, Inc., (© 2016 International Society for Autism Research, Wiley Periodicals, Inc.)

Autism spectrum disorder (ASD) has been postulated to involve impaired neuronal cooperation in large-scale neural networks, including cortico-cortical interhemispheric circuitry. In the context of ASD, alterations in both peripheral and central auditory processes have also attracted a great deal of interest because these changes appear to represent pathophysiological processes; therefore, many prior studies have focused on atypical auditory responses in ASD. The auditory evoked field (AEF), recorded by magnetoencephalography, and the synchronization of these processes between right and left hemispheres was recently suggested to reflect various cognitive abilities in children. However, to date, no previous study has focused on AEF synchronization in ASD subjects. To assess global coordination across spatially distributed brain regions, the analysis of Omega complexity from multichannel neurophysiological data was proposed. Using Omega complexity analysis, we investigated the global coordination of AEFs in 3-8-year-old typically developing (TD) children (n = 50) and children with ASD (n = 50) in 50-ms time-windows. Children with ASD displayed significantly higher Omega complexities compared with TD children in the time-window of 0-50 ms, suggesting lower whole brain synchronization in the early stage of the P1m component. When we analyzed the left and right hemispheres separately, no significant differences in any time-windows were observed. These results suggest lower right-left hemispheric synchronization in children with ASD compared with TD children. Our study provides new evidence of aberrant neural synchronization in young children with ASD by investigating auditory evoked neural responses to the human voice.

Extensive evidence shows that a core neurobiological mechanism of autism spectrum disorder (ASD) involves aberrant neural connectivity. Recent advances in the investigation of brain signal variability have yielded important information about neural network mechanisms. That information has been applied fruitfully to the assessment of aging and mental disorders. Multiscale entropy (MSE) analysis can characterize the complexity inherent in brain signal dynamics over multiple temporal scales in the dynamics of neural networks. For this investigation, we sought to characterize the magnetoencephalography (MEG) signal variability during free watching of videos without sound using MSE in 43 children with ASD and 72 typically developing controls (TD), emphasizing early childhood to older childhood: a critical period of neural network maturation. Results revealed an age-related increase of brain signal variability in a specific timescale in TD children, whereas atypical age-related alteration was observed in the ASD group. Additionally, enhanced brain signal variability was observed in children with ASD, and was confirmed particularly for younger children. In the ASD group, symptom severity was associated region-specifically and timescale-specifically with reduced brain signal variability. These results agree well with a recently reported theory of increased brain signal variability during development and aberrant neural connectivity in ASD, especially during early childhood. Results of this study suggest that MSE analytic method might serve as a useful approach for characterizing neurophysiological mechanisms of typical-developing and its alterations in ASD through the detection of MEG signal variability at multiple timescales., (© 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.)

Magnetoencephalography (MEG) is a non-invasive neuroimaging technique that provides a measure of cortical neural activity on a millisecond timescale with high spatial resolution. MEG has been clinically applied to various neurological diseases, including epilepsy and cognitive dysfunction. In the past decade, MEG has also emerged as an important investigatory tool in neurodevelopmental studies. It is therefore an opportune time to review how MEG is able to contribute to the study of atypical brain development. We limit this review to autism spectrum disorder (ASD). The relevant published work for children was accessed using PubMed on 5 January 2015. Case reports, case series, and papers on epilepsy were excluded. Owing to their accurate separation of brain activity in the right and left hemispheres and the higher accuracy of source localization, MEG studies have added new information related to auditory-evoked brain responses to findings from previous electroencephalography studies of children with ASD. In addition, evidence of atypical brain connectivity in children with ASD has accumulated over the past decade. MEG is well suited for the study of neural activity with high time resolution even in young children. Although further studies are still necessary, the detailed findings provided by neuroimaging methods may aid clinical diagnosis and even contribute to the refinement of diagnostic categories for neurodevelopmental disorders in the future., (© 2015 The Authors. Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology.)

Aims: Autism spectrum disorder (ASD) is often described as comprising an unusual brain growth pattern and aberrant brain lateralization. Although it is important to study the pathophysiology of the developing ASD cortex, examples of physiological brain lateralization in young children with ASD have yet to be well examined., Methods: Thirty-eight boys with ASD (aged 3-7 years) and 38 typically developing (TD) boys (aged 3-8 years) concentrated on video programs and their brain activities were measured non-invasively. We employed a customized child-sized magnetoencephalography system in which the sensors were located as close to the brain as possible for optimal recording in young children. To produce a credible laterality index of the brain oscillations, we defined two clusters of sensors corresponding to the right and left hemispheres. We focused on the laterality index ([left - right]/[left+right]) of the relative power band in seven frequency bands., Results: The TD group displayed significantly rightward lateralized brain oscillations in the theta-1 frequency bands compared to the ASD group., Conclusions: This is the first study to demonstrate unusual brain lateralization of brain oscillations measured by magnetoencephalography in young children with ASD., (© 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.)

Application of graph theory to analysis of functional networks in the brain is an important research trend. Extensive research on the resting state has shown a "small-world" organization of the brain network as a whole. However, the small-worldness of children's brain networks in a working state has not yet been well characterized. In this paper, we used a custom-made, child-sized magnetoencephalography (MEG) device to collect data from children while they were watching cartoon videos. Network structures were analyzed and compared with scores on the Kaufman Assessment Battery for Children (K-ABC). The results of network analysis showed that (1) the small-world scalar showed a negative correlation with the simultaneous processing raw score, a measure of visual processing (Gv) ability, and (2) the children with higher simultaneous processing raw scores possessed network structures that can be more efficient for local information processing than children with lower scores. These results were compatible with previous studies on the adult working state. Additional results obtained from further analysis of the frontal and occipital lobes indicated that high cognitive performance could represent better local efficiency in task-related sub-networks. Under free viewing of cartoon videos, brain networks were no longer confined to their strongest small-world states; connections became clustered in local areas such as the frontal and occipital lobes, which might be a more useful configuration for handling visual processing tasks., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Optimal brain sensitivity to the fundamental frequency (F0) contour changes in the human voice is important for understanding a speaker's intonation, and consequently, the speaker's attitude. However, whether sensitivity in the brain's response to a human voice F0 contour change varies with an interaction between an individual's traits (i.e., autistic traits) and a human voice element (i.e., presence or absence of communicative action such as calling) has not been investigated. In the present study, we investigated the neural processes involved in the perception of F0 contour changes in the Japanese monosyllables "ne" and "nu." "Ne" is an interjection that means "hi" or "hey" in English; pronunciation of "ne" with a high falling F0 contour is used when the speaker wants to attract a listener's attention (i.e., social intonation). Meanwhile, the Japanese concrete noun "nu" has no communicative meaning. We applied an adaptive spatial filtering method to the neuromagnetic time course recorded by whole-head magnetoencephalography (MEG) and estimated the spatiotemporal frequency dynamics of event-related cerebral oscillatory changes in beta band during the oddball paradigm. During the perception of the F0 contour change when "ne" was presented, there was event-related de-synchronization (ERD) in the right temporal lobe. In contrast, during the perception of the F0 contour change when "nu" was presented, ERD occurred in the left temporal lobe and in the bilateral occipital lobes. ERD that occurred during the social stimulus "ne" in the right hemisphere was significantly correlated with a greater number of autistic traits measured according to the Autism Spectrum Quotient (AQ), suggesting that the differences in human voice processing are associated with higher autistic traits, even in non-clinical subjects.

A subset of individuals with autism spectrum disorder (ASD) performs more proficiently on certain visual tasks than may be predicted by their general cognitive performances. However, in younger children with ASD (aged 5 to 7), preserved ability in these tasks and the neurophysiological correlates of their ability are not well documented. In the present study, we used a custom child-sized magnetoencephalography system and demonstrated that preserved ability in the visual reasoning task was associated with rightward lateralisation of the neurophysiological connectivity between the parietal and temporal regions in children with ASD. In addition, we demonstrated that higher reading/decoding ability was also associated with the same lateralisation in children with ASD. These neurophysiological correlates of visual tasks are considerably different from those that are observed in typically developing children. These findings indicate that children with ASD have inherently different neural pathways that contribute to their relatively preserved ability in visual tasks.

Previously, we demonstrated that CD38, a transmembrane protein with ADP-ribosyl cyclase activity, plays a critical role in mouse social behavior by regulating the release of oxytocin (OXT), which is essential for mutual recognition. When CD38 was disrupted, social amnesia was observed in Cd38 knockout mice. The autism spectrum disorders (ASDs), characterized by defects in reciprocal social interaction and communication, occur either sporadically or in a familial pattern. However, the etiology of ASDs remains largely unknown. Therefore, the theoretical basis for pharmacological treatments has not been established. Hence, there is a rationale for investigating single nucleotide polymorphisms (SNPs) in the human CD38 gene in ASD subjects. We found several SNPs in this gene. The SNP rs3796863 (C>A) was associated with high-functioning autism (HFA) in American samples from the Autism Gene Resource Exchange. Although this finding was partially confirmed in low-functioning autism subjects in Israel, it has not been replicated in Japanese HFA subjects. The second SNP of interest, rs1800561 (4693C>T), leads to the substitution of an arginine (R) at codon 140 by tryptophan (W; R140W) in CD38. This mutation was found in four probands of ASD and in family members of three pedigrees with variable levels of ASD or ASD traits. The plasma levels of OXT in ASD subjects with the R140W allele were lower than those in ASD subjects lacking this allele. The OXT levels were unchanged in healthy subjects with or without this mutation. One proband with the R140W allele receiving intranasal OXT for approximately 3years showed improvement in areas of social approach, eye contact and communication behaviors, emotion, irritability, and aggression. Five other ASD subjects with mental deficits received nasal OXT for various periods; three subjects showed improved symptoms, while two showed little or no effect. These results suggest that SNPs in CD38 may be possible risk factors for ASD by abrogating OXT function and that some ASD subjects can be treated with OXT in preliminary clinical trials., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

If the brain structural coordinates could be estimated using the individual head shape, magnetoencephalography and near-infrared spectroscopy would be more ideal brain functional imaging methods especially for young human children. First, we propose an algorithm to estimate brain coordinates with reference to the head surface shape in preschool children. Second, we examined its spatial error range using a leave-one-out procedure within 38 samples of child head and brain structures. The mean error of landmarks was 13.6±5.3 mm on the head surface and 18.5±12.4 mm in the intracranial structure between estimated and actual brain coordinates.

Recent neuroimaging studies support the view that a left-lateralized brain network is crucial for language development in children. However, no previous studies have demonstrated a clear link between lateralized brain functional network and language performance in preschool children. Magnetoencephalography (MEG) is a noninvasive brain imaging technique and is a practical neuroimaging method for use in young children. MEG produces a reference-free signal, and is therefore an ideal tool to compute coherence between two distant cortical rhythms. In the present study, using a custom child-sized MEG system, we investigated brain networks while 78 right-handed preschool human children (32-64 months; 96% were 3-4 years old) listened to stories with moving images. The results indicated that left dominance of parietotemporal coherence in theta band activity (6-8 Hz) was specifically correlated with higher performance of language-related tasks, whereas this laterality was not correlated with nonverbal cognitive performance, chronological age, or head circumference. Power analyses did not reveal any specific frequencies that contributed to higher language performance. Our results suggest that it is not the left dominance in theta oscillation per se, but the left-dominant phase-locked connectivity via theta oscillation that contributes to the development of language ability in young children.

Brain β-amyloid (Aβ) deposition during normal aging is highlighted as an initial pathogenetic event in the development of Alzheimer's disease. Many recent brain imaging studies have focused on areas deactivated during cognitive tasks [the default mode network (DMN), i.e., medial frontal gyrus/anterior cingulate cortex and precuneus/posterior cingulate cortex], where the strength of functional coordination was more or less affected by cerebral Aβ deposits. In the present positron emission tomography study, to investigate whether regional glucose metabolic alterations and Aβ deposits seen in nondemented elderly human subjects (n = 22) are of pathophysiological importance in changes of brain hemodynamic coordination in DMN during normal aging, we measured cerebral glucose metabolism with [(18)F]FDG, Aβ deposits with [(11)C]PIB, and regional cerebral blood flow during control and working memory tasks by H(2)(15)O on the same day. Data were analyzed using both region of interest and statistical parametric mapping. Our results indicated that the amount of Aβ deposits was negatively correlated with hemodynamic similarity between medial frontal and medial posterior regions, and the lower similarity was associated with poorer working memory performance. In contrast, brain glucose metabolism was not related to this medial hemodynamic similarity. These findings suggest that traceable Aβ deposition, but not glucose hypometabolism, in the brain plays an important role in occurrence of neuronal discoordination in DMN along with poor working memory in healthy elderly people.

Patients with panic disorder (PD) have a bias to respond to normal stimuli in a fearful way. This may be due to the preactivation of fear-associated networks prior to stimulus perception. Based on EEG, we investigated the difference between patients with PD and normal controls in resting state activity using features of transiently stable brain states (microstates). EEGs from 18 drug-naive patients and 18 healthy controls were analyzed. Microstate analysis showed that one class of microstates (with a right-anterior to left-posterior orientation of the mapped field) displayed longer durations and covered more of the total time in the patients than controls. Another microstate class (with a symmetric, anterior-posterior orientation) was observed less frequently in the patients compared to controls. The observation that selected microstate classes differ between patients with PD and controls suggests that specific brain functions are altered already during resting condition. The altered resting state may be the starting point of the observed dysfunctional processing of phobic stimuli.

Background: Sialyltransferase 8B (SIAT8B) and 8D (SIAT8D) are two polysialyltransferases that catalyze the transfer of polysialic acid (PSA) to the neural cell adhesion molecule 1 (NCAM1). PSA modification of NCAM1 plays an important role in neurodevelopment of the brain and disruption of this process is postulated as an etiologic factor in psychiatric disorders. Altered levels of the PSA-NCAM1 in the brain of schizophrenics have been reported, suggesting a role for this molecule in the disorder., Methods: We performed an association study of single nucleotide polymorphisms (SNPs) within SIAT8B and SIAT8D, using 188 schizophrenics and 156 age and gender matched controls. All genotypes were determined by polymerase chain reaction (PCR) amplification and direct sequencing., Results: Two polymorphisms, -1126T > C and -851T > C, located in the promoter region of SIAT8B showed nominally significant association with schizophrenia (allelic associations, p = .014 and p = .007, respectively), and haplotypes constructed from three additional SNPs located in the same linkage disequilibrium block were associated with schizophrenia. Furthermore an in vitro promoter assay revealed that a reporter construct containing a risk haplotype for SIAT8B had significantly higher transcriptional activity compared with one containing a protective haplotype (p = .021). In contrast, no significant association was observed between any variations in SIAT8D and schizophrenia., Conclusions: The present study suggests that functional promoter SNPs of SIAT8B could confer a risk for schizophrenia in the Japanese population.

Context: In animals, methamphetamine is known to have a neurotoxic effect on serotonin neurons, which have been implicated in the regulation of mood, anxiety, and aggression. It remains unknown whether methamphetamine damages serotonin neurons in humans., Objective: To investigate the status of brain serotonin neurons and their possible relationship with clinical characteristics in currently abstinent methamphetamine abusers., Design: Case-control analysis., Setting: A hospital research center., Participants: Twelve currently abstinent former methamphetamine abusers (5 women and 7 men) and 12 age-, sex-, and education-matched control subjects recruited from the community., Interventions: The brain regional density of the serotonin transporter, a structural component of serotonin neurons, was estimated using positron emission tomography and trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([(11)C](+)McN-5652). Estimates were derived from region-of-interest and statistical parametric mapping methods, followed by within-case analysis using the measures of clinical variables., Main Outcome Measures: The duration of methamphetamine use, the magnitude of aggression and depressive symptoms, and changes in serotonin transporter density represented by the [(11)C](+)McN-5652 distribution volume., Results: Methamphetamine abusers showed increased levels of aggression compared with controls. Region-of-interest and statistical parametric mapping analyses revealed that the serotonin transporter density in global brain regions (eg, the midbrain, thalamus, caudate, putamen, cerebral cortex, and cerebellum) was significantly lower in methamphetamine abusers than in control subjects, and this reduction was significantly inversely correlated with the duration of methamphetamine use. Furthermore, statistical parametric mapping analyses indicated that the density in the orbitofrontal, temporal, and anterior cingulate areas was closely associated with the magnitude of aggression in methamphetamine abusers., Conclusions: Protracted abuse of methamphetamine may reduce the density of the serotonin transporter in the brain, leading to elevated aggression, even in currently abstinent abusers.

Acetaldehyde binds to some proteins and becomes a Schiff base. It is assumed that after the consumption of ethanol the acetaldehyde binds to the proteins to form adducts, and such acetaldehyde adducts are associated with organ diseases. We investigated the detection of acetaldehyde adducts in the brain region of a human alcoholics. Brain samples collected from an alcoholic autopsied case were used. Determination of acetaldehyde adducts was performed using a fluorescence immmunohistochemical staining method with antibodies against acetaldehyde adducts. We demonstrated acetaldehyde adducts in the frontal cortex and the midbrain of an alcoholics. Our studies showed that an acetaldehyde adduct was produced in the brain of alcoholics.

(1)The basal ganglia circuitry mediates a wide rage of brain functions such as motor control, behavioral planning, and reward prediction. Dopamine (DA) transmission plays an essential role in the regulation of these brain functions. DA action not only regulates the firing activity of target neurons but also is involved in the pattern formation of their firing. The striatopallidal neurons containing dopamine D(2) receptor plays a dual role in motor coordination dependent on DA transmission. (2)Activation of presynaptic D(2)-like receptors on GABAergic terminals onto striatal cholinergic interneurons selectively blocks N-type Ca(2+) channels, thereby inhibiting GABA release. In addition, contribution of N-type channels and D(2)-like receptor-mediated presynaptic inhibition decreases in parallel with development, implying some relationship between basal ganglia-related function or dysfunction and age. (3)As an approach to determine dopamine neuronal activity, we monitored neuronal activities by measuring cytosolic Ca(2+) concentration in VTA dopamine neurons. The present study indicates that VTA dopamine neurons are the direct targets of orexin-A and psychostimulants, and the [Ca(2+)](i) signaling is thought to play a significant role in the regulation of dopamine neuronal activity. (4)The excitability of neostriatal neurons is regulated by a balance of glutamatergic and dopaminergic inputs. Glutamate has been shown to modulate dopaminergic signaling. Studies on the regulation of DARPP-32 phosphorylation by glutamate provide a molecular basis for both the synergistic and antagonistic effects of glutamate on dopaminergic signaling. (5) Impairment of function of stem/progenitor cells may be implicated in the pathogenesis of schizophrenia. To test this hypothesis, several experiments are currently ongoing in our laboratory, and the preliminary results obtained are described here.

In this study, we examined the effect of the s.c. administration of (+/-) 3,4-methylenedioxymethamphetamine (MDMA) or saline on locomotor activity and Fos expression following the bilateral destruction of hippocampal dentate granule cells by colchicine in rats. The lesioned animals, when administered s.c. saline, showed a significantly greater increase in locomotor activity compared to the intact animals, and revealed a marginally significant level of increased locomotor activity compared to the sham-lesioned animals. In addition, when the lesioned animals were given s.c. saline or MDMA, there was a significant increase in Fos expression in the nucleus accumbens core, but not in the medial prefrontal cortex, dorsolateral prefrontal cortex, anterior cingulate cortex, piriform cortex, dorsal striatum, or nucleus accumbens shell, compared to the intact and sham-lesioned animals. Overall, these results suggest that the nucleus accumbens core may be involved in the enhancement of locomotor activity induced by the injection of saline alone (stress loading) or MDMA following bilateral destruction of hippocampal dentate granule cells by colchicine.

In the present study, we examined the effect of the novel sigma receptor ligand NE-100 on 5-hydroxytryptamine-2A (5-HT2A) receptor binding in rat brain using an in vivo approach. Rats received intraperitoneal injections of either vehicle (1 ml/kg) or NE-100 (3 mg/kg) twice daily for 14 days. The in vivo binding of [3H]RP 62203, a selective 5-HT2A receptor radioligand, to 5-HT2A receptors in the rat brain was examined at 1, 3 or 7 days after final treatment. The specific binding of [3H]RP 62203 in the frontal cortex, parietal cortex and occipital cortex 1 day after subchronic administration of NE-100 was significantly increased as compared to animals treated with vehicle. In contrast, specific binding in the frontal cortex and parietal cortex 3 days after subchronic administration of NE-100 was significantly decreased as compared with the vehicle treated group. Seven days after the last injection of NE-100 or vehicle, there were no significant differences between the NE-100 and vehicle treated groups in [3H]RP 62203 binding in all the regions examined except for the hippocampus. These findings indicate that subchronic treatment with NE-100 may regulate the in vivo binding characteristics of 5-HT2A receptors in the cerebral cortex of rat brain.

High-affinity N-methyl-D-aspartate (NMDA) receptor antagonists like MK-801 are known to induce the heat shock protein, HSP70, in the posterior cingulate cortex and retrosplenial cortex of rat brain. Memantine, which is a low affinity uncompetitive NMDA receptor antagonist, has been used in the treatment of Parkinson's disease in Europe. The faster kinetics of memantine in blocking and unblocking the NMDA receptor-operated ion channel as opposed to high-affinity NMDA antagonists like MK-801 has been thought to account for the safety of memantine. The present study evaluated the neurotoxic potential of memantine and amantadine using the induction of HSP70 immunoreactivity in rat brain. Memantine (25, 50, 75 mg/kg) induced HSP70 in the posterior cingulate, retrosplenial cortex and dentate gyrus of rat brain. In contrast, amantadine (50, 100, 200 mg/kg) did not induce HSP70 in the rat brain. These results suggest that memantine has an antagonistic effect at NMDA receptor in vivo, and raises the possibility that high doses of memantine may cause neuronal damage similar to those observed with other high-affinity NMDA receptor antagonists.

The interactions of selective serotonin reuptake inhibitors and tricyclic antidepressants with subtypes of sigma receptors were investigated. The rank order of affinity (Ki values) from competition experiments of [3H](+)-pentazocine binding to sigma 1 sites was: fluvoxamine > sertraline > S(+)-fluoxetine > (+/-)-fluoxetine > citalopram > imipramine > paroxetine > desipramine > R(-)-fluoxetine > (+/-)-norfluoxetine. The Ki values of all drugs for sigma 2 sites were more than 1000 nM. Furthermore, all drugs were more potent at sigma 1 sites than at sigma 2 sites. These findings suggest that sigma receptors (sigma 1 site) may play, in some way, a role in the actions of selective serotonin reuptake inhibitors.

Serial assessments of regional cerebral blood flow were performed using 123I-IMP SPECT in two schizophrenic and three schizophreniform patients with persistent auditory hallucination. The initial SPECT study in the period with prominent auditory hallucination revealed an increased accumulation of 123I-IMP in the left superior temporal area which corresponded to the auditory association cortex. In the follow-up SPECT study performed after clinical improvement, the distribution of 123I-IMP had normalized. One of the case with schizophrenia showed a similar increased uptake of 123I-IMP in the left superior temporal area in the third SPECT scan performed when a psychotic relapse with auditory hallucination occurred. MRI scans in two of the five patients demonstrated reduced volume of the temporal lobes. These findings suggest that the auditory hallucinations in schizophrenia may be involved in functional hyperactivity in the left superior temporal cortex which might be based partly on structural abnormalities in the temporal lobes.

Acute effects of several antiepileptic drugs on low-frequency amygdaloid-kindled seizures were assessed. The number of stimulating pulses required for the provocation of epileptic afterdischarge (pulse-number threshold, PNT) was used as an indicator for the seizure-generating threshold. The duration of epileptic afterdischarge (AD duration) was used as an indicator for the severity of the induced seizures. Phenytoin (PHT) and carbamazepine (CBZ) reduced AD duration more than did elevating PNT. Conversely, phenobarbital (PB) and diazepam (DZP) elevated PNT more than did reducing AD duration. Weak effects on the two indicators, valproic acid (VPA) and ethosuximide (ESM), were observed. Low-frequency kindling may be a useful experimental model of epilepsy in drug-assessments.

Psychostimulant drugs have been reported to increase the expression of some immediate-early genes in the brain. In the present study, immunohistochemical techniques were used to assess the pattern of Fos protein produced by 3,4-methylenedioxymethamphetamine (MDMA) in several brain regions. Furthermore, we also studied the role of the dopamine D and D receptors and the N-methyl- D-aspartate (NMDA) receptor in the induction of Fos protein by MDMA. A single administration of MDMA (5, 10 or 20 mg/kg) caused marked induction of Fos-immunoreactivity in several regions including frontal cortex, striatum and olfactory tubercle of rat brain, in a dose-dependent manner. However, in the hippocampus and cerebellum, there were few or no Fos immunoreactive cells induced by MDMA. Furthermore, the induction of Fos protein in the striatum and olfactory tubercle after administration of MDMA (10 mg/kg) was blocked by pre-treatment with the dopamine D receptor antagonist SCH 23390 (1 mg/kg) or the NMDA receptor antagonist dizocilpine (1 mg/kg), but not by the dopamine D receptor antagonist (-)-sulpiride (100 mg/kg). However, the induction of Fos protein in the frontal cortex and hippocampus by MDMA was unaltered by pretreatment with SCH 23390 (1 mg/kg) or (-)-sulpiride (100 mg/kg). These results suggest that MDMA induces the expression of Fos protein in several regions of rat brain, and that the expression of Fos protein by MDMA in the striatum and olfactory tubercle appears to be mediated at least in part by the dopamine D and NMDA receptors. [ABSTRACT FROM AUTHOR]