DOI： 10.1007/s00213-019-05337-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Verlag  

Background: Tramadol is an analgesic with monoamine reuptake inhibition and μ-opioid receptor activation. Although tramadol has been widely used for treatment of various pain conditions, there is controversy over the risk of abuse potential. We examined the effects of tramadol on the reward system in humans using functional magnetic resonance imaging (fMRI) to assess the potential of tramadol for drug abuse or dependence. Methods: A randomized, double-blind, placebo-controlled, crossover study was conducted for 19 healthy adults under tramadol or placebo. In association with subjective mood questionnaires, monetary incentive delay (MID) task was performed to assess the neural response to reward anticipation during fMRI. Subjective mood measures and blood oxygenation level-dependent (BOLD) signal during gain and loss anticipation were compared between tramadol and placebo. Results: Tramadol significantly reduced anxiety (Z = − 2.513, p = 0.012) and enhanced vigor (Z = − 2.725, p = 0.006) compared with placebo. By Mood Rating Scale, tramadol provoked contented (Z = − 2.316, p = 0.021), relaxed (Z = − 2.236, p = 0.025), and amicable feelings (Z = − 2.015, p = 0.044) as well as increased alertness (Z = − 1.972, p = 0.049) and contentedness domains (Z = − 2.174, p = 0.030) compared with placebo. Several brain regions including nucleus accumbens (NAc) were activated during gain anticipation in the MID task under both tramadol and placebo. Tramadol increased the %BOLD signal change in NAc at +\500 cue significantly more than the placebo (Z = − 2.295, p = 0.022). Conclusion: Tramadol enhances the reward system and thereby may have abuse potential or precipitate drug abuse in human.

DOI： 10.1007/s00213-018-4955-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Modafinil is a wake-promoting agent and has been reported to be effective in improving attention in patients with attentional disturbance. However, neural substrates underlying the modafinil effects on attention are not fully understood.
We employed a functional magnetic resonance imaging (fMRI) study with the attention network test (ANT) task in healthy adults and examined which networks of attention are mainly affected by modafinil and which neural substrates are responsible for the drug effects.
We used a randomized placebo-controlled within-subjects cross-over design. Twenty-three healthy adults participated in two series of an fMRI study, taking either a placebo or modafinil. The participants performed the ANT task, which is designed to measure three distinct attentional networks, alerting, orienting, and executive control, during the fMRI scanning. The effects of modafinil on behavioral performance and regional brain activity were analyzed.
We found that modafinil enhanced alerting performance and showed greater alerting network activity in the left middle and inferior occipital gyri as compared with the placebo. The brain activations in the occipital regions were positively correlated with alerting performance.
Modafinil enhanced alerting performance and increased activation in the occipital lobe in the alerting network possibly relevant to noradrenergic activity during the ANT task. The present study may provide a rationale for the treatment of patients with distinct symptoms of impaired attention.

DOI： 10.1007/s00213-017-4614-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FRONTIERS RESEARCH FOUNDATION  

Recent neuroimaging studies have demonstrated that Contactin-associated protein-like2 (CNTNAP2) polymorphisms affect left-hemispheric function of language processing in healthy individuals, but no study has investigated the influence of these polymorphisms on right-hemispheric function involved in human voice perception. Further, although recent reports suggest that determination of handedness is influenced by genetic effect, the interaction effect between handedness and CNTNAP2 polymorphisms for brain activity in human voice perception and language processing has not been revealed. We aimed to investigate the interaction effect of handedness and CNTNAP2 polymorphisms in respect to brain function for human voice perception and language processing in healthy individuals. Brain function of 108 healthy volunteers (74 right-handed and 34 non-right-handed) was examined while they were passively listening to reverse sentences (rSEN), identifiable non-vocal sounds (SND), and sentences (SEN). Full factorial design analysis was calculated by using three factors: (1) rs7794745 (A/A or A/T), (2) rs2710102 [G/G or A carrier (A/G and A/A)], and (3) voice-specific response (rSEN or SND). The main effect of rs7794745 (A/A or A/T) was significantly revealed at the right middle frontal gyrus (MFG) and bilateral superior temporal gyrus (STG). This result suggests that rs7794745 genotype affects voice-specific brain function. Furthermore, interaction effect was significantly observed among MFG-STG activations by human voice perception, rs7794745 (A/A or A/T), and handedness. These results suggest that CNTNAP2 polymorphisms could be one of the important factors in the neural development related to vocal communication and language processing in both right-handed and non-right-handed healthy individuals.

DOI： 10.3389/fnbeh.2015.00087

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

The nucleus accumbens (NAc) works as a key brain structure of the reward system, in which reward-related neural activity is well correlated with dopamine release from mesolimbic dopaminergic neurons.
Since modafinil can modulate dopaminergic transmission through re-uptake inhibition of dopamine, we investigated whether modafinil affects the reward-related brain activity in the NAc in healthy subjects.
Twenty healthy participants underwent two series of functional magnetic resonance imaging while performing monetary incentive delay task in which they were cued to anticipate and respond to a rapidly presented target to gain or avoid losing varying amounts of money, under modafinil or placebo condition. Blood oxygenation-level dependent (BOLD) activation signals during gain and loss anticipations were analyzed in the NAc as an a priori region of interest as well as the whole brain.
Modafinil significantly changed subjective feelings toward positive ones. The activation of BOLD signals was observed during gain anticipation under the placebo and modafinil conditions in the left and bilateral NAc, respectively. The modafinil condition showed significantly higher BOLD signal change at the highest gain (+Ayen500) cue compared to the placebo condition.
The present study showed that modafinil affects reward processing in the NAc in healthy subjects through enhancing more positive anticipation, and it may provide a basis for the use of this drug for treating anhedonia observed in psychiatric disorders.

DOI： 10.1007/s00213-014-3499-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CAMBRIDGE UNIV PRESS  

Tramadol is used for the treatment of pain, and it is generally believed to activate the -opioid receptor and inhibit serotonin (5-HT) and norepinephrine (NE) transporters. Recent findings from animal experiments suggest that 5-HT reuptake inhibition in brain is related to pain reduction. However, there has been no report of 5-HT transporter (5-HTT) occupancy by tramadol at clinical doses in humans. In the present study, we investigated 5-HTT occupancy by tramadol in five subjects receiving various doses of tramadol by using positron emission tomography (PET) scanning with the radioligand [C-11]DASB. Our data showed that mean 5-HTT occupancies in the thalamus by single doses of tramadol were 34.7% at 50mg and 50.2% at 100mg. The estimated median effective dose (ED50) of tramadol was 98.1mg, and the plasma concentration was 0.33g/ml 2h after its administration; 5-HTT occupancy by tramadol was dose-dependent. We estimated 5-HTT occupancy at 78.7% upon taking an upper limit dose (400mg) of tramadol. The results of the present study support the finding that 5-HTT inhibition is involved in the mechanism underlying the analgesic effect of tramadol in humans, and a clinical dose of tramadol sufficiently inhibits 5-HTT reuptake; this inhibition is similar to that shown by selective serotonin reuptake inhibitors (SSRIs).

DOI： 10.1017/S1461145713001764

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Mazindol, an appetite suppressant, inhibits the reuptake of dopamine in the synaptic cleft. It has been considered that mazindol might enhance dopamine transmission in the human brain. However, there has been no study that investigated the extracellular dopamine concentration in vivo.
Using positron emission tomography (PET), we aimed to measure the effect of mazindol on the extracellular dopamine concentration and to evaluate how mazindol affects the dopamine system in the healthy human brain.
Eleven healthy individuals (six males, five females, age 30.9 +/- 4.9 years) were enrolled in this study. Each participant was scanned with [C-11]raclopride on 1 day without any medicine as baseline condition, and on another day with mazindol as drug condition. In the drug condition, participants took mazindol 0.5 mg (N = 5) or 1.5 mg (N = 6) 2 h before the PET scan. Plasma concentrations of mazindol were measured before the injection of [C-11]raclopride, and urine concentrations of mazindol were measured after the scan.
After taking mazindol, the calculated decrease in binding potential (Delta BP) in the striatum was 1.74 % for 0.5 mg and 8.14 for 1.5 mg, and the correlation with the blood concentration of mazindol was significant (P = 0.0016, R (2) = 0.69). Delta BP was not significantly correlated with the urine concentration of mazindol (P = 0.84, R (2) = 0.005).
Mazindol increased the extracellular concentration of dopamine in the human brain, and its effect was dose dependent. A single administration of mazindol, even at usual dosage, elevated dopamine concentration similarly to other addictive drugs, suggesting that the risk of dependence may increase with the mazindol dose.

DOI： 10.1007/s00213-013-3392-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1017/S1461145713001612

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1017/S1461145712001678

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

The hippocampal dentate gyrus has been implicated in a neuronal basis of antidepressant action. We have recently shown a distinct form of neuronal plasticity induced by the serotonergic antidepressant fluoxetine, that is, a reversal of maturation of the dentate granule cells in adult mice. This "dematuration'' is induced in a large population of dentate neurons and maintained for at least one month after withdrawal of fluoxetine, suggesting long-lasting strong influence of dematuration on brain functioning. However, reliable induction of dematuration required doses of fluoxetine higher than suggested optimal doses for mice (10 to 18 mg/kg/day), which casts doubt on the clinical relevance of this effect. Since our previous studies were performed in naive mice, in the present study, we reexamined effects of fluoxetine using mice treated with chronic corticosterone that model neuroendocrine pathophysiology associated with depression. In corticosterone-treated mice, fluoxetine at 10 mg/kg/day downregulated expression of mature granule cell markers and attenuated strong frequency facilitation at the synapse formed by the granule cell axon mossy fiber, suggesting the induction of granule cell dematuration. In addition, fluoxetine caused marked enhancement of dopaminergic modulation at the mossy fiber synapse. In vehicle-treated mice, however, fluoxetine at this dose had no significant effects. The plasma level of fluoxetine was comparable to that in patients taking chronic fluoxetine, and corticosterone did not affect it. These results indicate that corticosterone facilitates fluoxetine-induced plastic changes in the dentate granule cells. Our finding may provide insight into neuronal mechanisms underlying enhanced responsiveness to antidepressant medication in certain pathological conditions.

DOI： 10.1371/journal.pone.0063662

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記述言語：英語   出版者・発行元：MEDICAL ASSOC NIPPON MEDICAL SCH  

DOI： 10.1272/jnms.79.318

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat mood and anxiety disorders. However, neuronal bases for both beneficial and adverse effects of SSRIs remain poorly understood. We have recently shown that the SSRI fluoxetine can reverse the state of maturation of hippocampal granule cells in adult mice. The granule cell "dematuration" is induced in a large population of granule cells, and greatly changes functional and physiological properties of these cells. Here we show that this unique form of neuronal plasticity is correlated with a distinct change in behavior of mice.
Results: We chronically treated adult male mice with fluoxetine, and examined its effect on several forms of behavior of mice. During fluoxetine treatments, mice showed a marked increase in day-to-day fluctuations of home cage activity levels that was characterized by occasional switching between hypoactivity and hyperactivity within a few days. This destabilized cage activity was accompanied by increased anxiety-related behaviors and could be observed up to 4 weeks after withdrawal from fluoxetine. As reported previously, the granule cell dematuration by fluoxetine includes a reduction of synaptic facilitation at the granule cell output, mossy fiber, synapse to the juvenile level. Mossy fiber synaptic facilitation examined electrophysiologically in acute hippocampal slices also remained suppressed after fluoxetine withdrawal and significantly correlated with the fluctuation of cage activity levels in individual mice. Furthermore, in mice lacking the 5-HT4 receptor, in which the granule cell dematuration has been shown to be attenuated, fluoxetine had no significant effect on the fluctuation of cage activity levels.
Conclusions: Our results demonstrate that the SSRI fluoxetine can induce marked day-to-day changes in activity levels of mice in the familiar environment, and that the dematuration of the hippocampal granule cells is closely associated with the expression of this destabilized behavior. Based on these results, we propose that the granule cell dematuration can be a potential cellular basis underlying switching-like changes in the behavioral state associated with SSRI treatments.

DOI： 10.1186/1756-6606-4-12

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Local anesthetics alleviate neuropathic pain in some cases in clinical practice, and exhibit longer durations of action than those predicted on the basis of the pharmacokinetics of their blocking effects on voltage-dependent sodium channels. Therefore, local anesthetics may contribute to additional mechanisms for reversal of the sensitization of nociceptive pathways that occurs in the neuropathic pain state. In recent years, spinal glial cells, microglia and astrocytes, have been shown to play critical roles in neuropathic pain, but their participation in the analgesic effects of local anesthetics remains largely unknown.
Results: Repetitive epidural administration of ropivacaine reduced the hyperalgesia induced by chronic constrictive injury of the sciatic nerve. Concomitantly with this analgesia, ropivacaine suppressed the increases in the immunoreactivities of CD11b and glial fibrillary acidic protein in the dorsal spinal cord, as markers of activated microglia and astrocytes, respectively. In addition, epidural administration of a TrkA-IgG fusion protein that blocks the action of nerve growth factor (NGF), which was upregulated by ropivacaine in the dorsal root ganglion, prevented the inhibitory effect of ropivacaine on microglia, but not astrocytes. The blockade of NGF action also abolished the analgesic effect of ropivacaine on neuropathic pain.
Conclusions: Ropivacaine provides prolonged analgesia possibly by suppressing microglial activation in an NGF-dependent manner and astrocyte activation in an NGF-independent manner in the dorsal spinal cord. Local anesthetics, including ropivacaine, may represent a new approach for glial cell inhibition and, therefore, therapeutic strategies for neuropathic pain.

DOI： 10.1186/1744-8069-7-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Aim: The aim of the present study was to investigate the effects of acute paroxetine administration on brain activity related to motivation.
Methods: Sixteen healthy subjects participated in a randomized, single-blind, no-drug/placebo-controlled, cross-over study. After administration of no drug, placebo or paroxetine (selective serotonin reuptake inhibitor; 20 mg), subjects underwent functional magnetic resonance imaging while performing a monetary incentive delay task. We analyzed the differences in brain activities of the reward anticipation/motor preparation period that are subject to motivational modulation. For this purpose, we subdivided the incentive trials on the basis of whether the reaction times (RT) were slower or faster than the subject's mean RT (slow RT and fast RT trials).
Results: No drug and placebo showed robust activation differences in the globus pallidus and putamen for the fast RT trials compared to the slow RT trials, whereas paroxetine showed none. Paroxetine showed significantly lower activations in the globus pallidus, insula, putamen and dorsolateral prefrontal cortex compared to no drug in the fast RT trials.
Conclusions: Paroxetine single acute administration diminished brain activity induced by motivation in healthy subjects. This may partially explain the increased lack of motivation seen in patients with relatively mild symptoms after taking a dose of paroxetine for the first time.

DOI： 10.1111/j.1440-1819.2011.02189.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATL ACAD SCIENCES  

Serotonergic antidepressant drugs have been commonly used to treat mood and anxiety disorders, and increasing evidence suggests potential use of these drugs beyond current antidepressant therapeutics. Facilitation of adult neurogenesis in the hippocampal dentate gyrus has been suggested to be a candidate mechanism of action of antidepressant drugs, but this mechanism may be only one of the broad effects of antidepressants. Here we show a distinct unique action of the serotonergic antidepressant fluoxetine in transforming the phenotype of mature dentate granule cells. Chronic treatments of adult mice with fluoxetine strongly reduced expression of the mature granule cell marker calbindin. The fluoxetine treatment induced active somatic membrane properties resembling immature granule cells and markedly reduced synaptic facilitation that characterizes the mature dentate-to-CA3 signal transmission. These changes cannot be explained simply by an increase in newly generated immature neurons, but best characterized as "dematuration" of mature granule cells. This granule cell dematuration developed along with increases in the efficacy of serotonin in 5-HT4 receptor-dependent neuromodulation and was attenuated in mice lacking the 5-HT4 receptor. Our results suggest that serotonergic antidepressants can reverse the established state of neuronal maturation in the adult hippocampus, and up-regulation of 5-HT4 receptor-mediated signaling may play a critical role in this distinct action of antidepressants. Such reversal of neuronal maturation could affect proper functioning of the mature hippocampal circuit, but may also cause some beneficial effects by reinstating neuronal functions that are lost during development.

DOI： 10.1073/pnas.0912690107

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Comprehending conversation in a crowd requires appropriate orienting and sustainment of auditory attention to and discrimination of the target speaker. While a multitude of cognitive functions such as voice perception and language processing work in concert to subserve this ability, it is still unclear which cognitive components critically determine successful discrimination of speech sounds under constantly changing auditory conditions. To investigate this, we present a functional magnetic resonance imaging (fMRI) study of changes in cerebral activities associated with varying challenge levels of speech discrimination. Subjects participated in a diotic listening paradigm that presented them with two news stories read simultaneously but independently by a target speaker and a distracting speaker of incongruent or congruent sex. We found that the voice of distracter of congruent rather than incongruent sex made the listening more challenging, resulting in enhanced activities mainly in the left temporal and frontal gyri. Further, the activities at the left inferior, left anterior superior and right superior loci in the temporal gyrus were shown to be significantly correlated with accuracy of the discrimination performance. The present results suggest that the subregions of bilateral temporal gyri play a key role in the successful discrimination of speech under constantly changing auditory conditions as encountered in daily life. (C) 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2010.02.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC NEUROSCIENCE  

Selective serotonin reuptake inhibitors (SSRIs) have been used to treat various psychiatric disorders. Although the cellular mechanisms underlying amelioration of particular symptoms are mostly unknown, recent studies have shown critical importance of the dentate gyrus of the hippocampus in behavioral effects of SSRIs in rodents. Here, we show that serotonin potentiates synaptic transmission between mossy fibers, the sole output of the dentate granule cells, and CA3 pyramidal cells in mouse hippocampal slices. This potentiation is mediated by activation of 5-HT4 receptors and intracellular cAMP elevation. A chronic treatment of mice with fluoxetine, a widely used SSRI, bidirectionally modulates the 5-HT-induced potentiation: Fluoxetine enhances the potentiation induced by lower concentrations of serotonin, while attenuates that by the higher concentration, which represents stabilization of synaptic 5-HT action. In contrast to the chronic treatment, an acute application of fluoxetine in slices induces a leftward shift in the dose-response curve of the 5-HT-induced potentiation. Thus, acute and chronic fluoxetine treatments have distinct effects on the serotonergic modulation of the mossy fiber synaptic transmission. Exposure of mice to novel environments induces increases in locomotor activity and hippocampal extracellular 5-HT levels. In mice chronically treated with fluoxetine, the novelty-induced hyperactivity is reduced without significant alterations in home cage activity and motor skills. Our results suggest that the chronic fluoxetine treatment can stabilize the serotonergic modulation of the central synaptic transmission, which may contribute to attenuation of hyperactive behaviors.

DOI： 10.1523/JNEUROSCI.1656-08.2008

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Neurotrophic factors (NFs) play a pivotal role in the development of the central nervous system. They are thus also suspected of being involved in the etiology of schizophrenia. Previous studies reported a decreased level of serum brain-derived neurotrophic factor (BDNF) in schizophrenia, whereas the association of epidermal growth factor (EGF) with this illness remains controversial. Using a two-site enzyme immunoassay, we conducted the simultaneous measurement of serum BDNF and EGF levels in a group of patients with chronic schizophrenia (N= 74) and a group of normal controls matched in age, body mass index, smoking habit and sex (N= 8 7). We found that, compared to normal controls, patients with chronic schizophrenia exhibited lower serum levels of both BDNF and EGF across all ages examined (21-59 years). The serum levels of BDNF and EGF were negatively correlated in the controls (r=-0.387, P=0.0002) but not in the patients. Clinical parameters such as duration of illness and psychiatric rating scale also showed no robust correlations with the NF levels. Collectively, these results suggest that pervasive, abnormal signaling of NFs underlies the pathophysiology of chronic schizophrenia. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2008.01.017

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

BACKGROUND: In clinical practice, the analgesic effects of epidurally administered local anesthetics on chronic pain sometimes outlast the duration of drug action expected from their pharmacokinetics. To investigate the underlying mechanisms of this prolonged effect, we examined the effects of ropivacaine, a local anesthetic, on pain-related behavior in a rat model of neuropathic pain. We also analyzed changes in the expression of nerve growth factor (NGF), which is involved in plasticity of the nociceptive circuit after nerve injury.
METHODS: In a rat model of neuropathic pain produced by chronic constrictive injury (CCI) of the sciatic nerve, thermal hyperalgesia, and mechanical allodynia were observed from Day 3 after surgery. Ropivacaine or saline was administered through an epidural catheter once a day, every day, and from Days 7-13 after the CCI operation. NGF content was measured in the L4 dorsal root ganglion, the hindpaw skin, the L4/5 dorsal spinal cord, and the sciatic nerve, using enzyme immunoassay.
RESULTS: The latency to withdrawal from thermal stimuli on the ipsilateral paw pads of CCI rats was significantly increased 4 days after the beginning of ropivacaine treatment, and thermal hyperalgesia was almost fully relieved. Similarly, mechanical allodynia was partially reduced after ropivacaine treatment. NGF content was increased in the L4 dorsal root ganglion on the ipsilateral, but not the contralateral, side, in CCI rats treated with ropivacaine.
CONCLUSION: Repetitive administration of ropivacaine into the epidural space in CCI rats exerts an analgesic effect, possibly by inducing a plastic change in the nociceptive circuit.

DOI： 10.1213/01.ane.0000296460.91012.51

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING  

The hippocampus has long been implicated in memory formation. Although accumulating evidence suggests involvement of the hippocampus in other brain functions including locomotor regulation and emotional processes, cellular and synaptic bases underlying these functions remain largely unknown. We here report that environmental manipulations in mice unveiled the association of locomotor activity with the hippocampal mossy fibre (MF) synaptic transmission. Electrophysiological recordings of synaptic responses were made using hippocampal slices prepared from mice whose behaviour had been analysed. Environmental enrichment induced parallel decreases in open-field locomotor activity and MF synaptic facilitation. Facilitation induced by paired-pulse stimulation at relatively long intervals (>= 200 ms) was selectively reduced while the basal synaptic efficacy and high-frequency transmission were unaffected. Social isolation caused a change in behaviour in an elevated plus-maze, but neither the open-field activity nor the MF synaptic transmission was significantly altered. Effects of dopamine, a neurotransmitter essential for locomotor regulation, on the MF synapse were also examined using these mice. Environmental manipulations did not cause significant changes in potentiation of the MF synaptic transmission induced by dopamine. However, analysis of behavioural and electrophysiological results in individual subjects revealed that locomotor activity negatively correlates with magnitude of the dopamine-induced potentiation. These results suggest that the MF synapse plays important roles in the regulation of locomotor activity. We propose that the MF synapse can serve as the synaptic model for certain forms of locomotor regulation, with potential importance for investigation of the pathophysiology of psychiatric diseases using animal models.

DOI： 10.1111/j.1460-9568.2006.05079

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記述言語：日本語   出版者・発行元：日本生物学的精神医学会・日本神経精神薬理学会  

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記述言語：日本語   出版者・発行元：日本生物学的精神医学会・日本神経精神薬理学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：BMJ PUBLISHING GROUP  

DOI： 10.1136/jnnp-2017-BNPA.80

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：BMJ PUBLISHING GROUP  

DOI： 10.1136/jnnp-2017-BNPA.55

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DOI： 10.1136/jnnp-2015-311750.64

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記述言語：日本語   出版者・発行元：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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記述言語：日本語   出版者・発行元：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

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記述言語：日本語   出版者・発行元：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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記述言語：日本語   出版者・発行元：(一社)日本歯科麻酔学会  

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記述言語：日本語   出版者・発行元：(一社)日本歯科麻酔学会  

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DOI： 10.1016/j.neures.2011.07.754

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記述言語：日本語   出版者・発行元：(一社)日本臨床神経生理学会  

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記述言語：日本語   出版者・発行元：(一社)日本臨床神経生理学会  

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記述言語：日本語  

J-GLOBAL

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記述言語：英語   出版者・発行元：日本神経化学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2010.07.2305

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SPRINGER TOKYO  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本臨床神経生理学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2009.09.1351

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SPRINGER TOKYO  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2009.09.145

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出版者・発行元：日本生理学会  

The dentate gyrus of the hippocampus has been implicated in behavioral effects of antidepressant drugs including selective serotonin reuptake inhibitors (SSRIs). The mossy fiber (MF) is the sole output of dentate granule cells and thus plays a pivotal role in regulation of hippocampal neuronal activity by the dentate gyrus. To test possible involvement of modification of the MF synapse in behavioral changes caused by SSRIs, we examined effects of chronic oral administration of fluoxetine, a widely used SSRI, on behaviors and the MF synaptic transmission in adult mice. Fluoxetine had multiple effects on behaviors and the MF synaptic transmission in a dose-dependent manner. At a lower dose, the fluoxetine treatment reduced activity of mice in a novel environment and affected modulation of the MF synaptic transmission by serotonin without noticeable effects on the synaptic transmission itself. At higher doses, however, it markedly increased fluctuation of home cage activity and anxiety-related behaviors, and also greatly reduced the large synaptic facilitation that is a characteristic of the mature MF synapse. This synaptic change was well correlated with the behavioral changes. In the dentate gyrus of mice treated with the higher dose of fluoxetine, expression of calbindin, a marker for the mature granule cells, was significantly reduced. These results indicate that fluoxetine at high doses can disrupt the maturation state of the dentate gyrus and the MF synaptic transmission in adult mice, which may underlie the destabilized behavior in the treated mice. <b>[J Physiol Sci. 2008;58 Suppl:S35]</b>

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER IRELAND LTD  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本核医学会  

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記述言語：日本語   出版者・発行元：国立精神・神経センター  

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記述言語：日本語   出版者・発行元：(一社)日本臨床神経生理学会  

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記述言語：日本語   出版者・発行元：(一社)日本臨床神経生理学会  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語  

J-GLOBAL

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