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Sae-Ung K.,Srinakharinwirot University | Ueda K.,Tokyo Institute of Psychiatry | Govitrapong P.,Mahidol University | Phansuwan-Pujito P.,Srinakharinwirot University
Journal of Pineal Research | Year: 2012

Alpha-synuclein (α-syn) is a neuronal protein that is involved in various degenerative disorders such as Parkinson's disease. It is found in the presynaptic terminals and perinuclear zones of many brain regions. Amphetamine (AMPH), a psychostimulant drug abused progressively more commonly in recent years, has been known to induce neurotoxicity in the central dopaminergic pathway, which is associated with increased oxidative stress. Recently, AMPH has been shown to significantly increase the level of α-syn in dopaminergic neuroblastoma cell cultures. Melatonin is recognized as an antioxidant for the nervous system. This study tested whether melatonin can attenuate the effect of AMPH on the expression of α-syn in the dopaminergic pathway of the neonatal rat. Four-day old postnatal rats (P4) were injected subcutaneously with either AMPH (increasing dose, 5-10 mg/kg daily) alone or AMPH with melatonin (2 mg/kg) daily at 10:00 AM for 7 consecutive days. As determined using Western blot, the level of α-syn was significantly increased in the substantia nigra, dorsal striatum, nucleus accumbens, and prefrontal cortex of the AMPH-treated group, while melatonin treatment either prior to AMPH or alone decreased the accumulation of the protein to 77%, 96%, 78%, and 77% of the control value, respectively. Furthermore, an immunofluorescent study showed that the α-syn-immunoreactivity increased noticeably in the nuclei of cell bodies and nerve terminals of the AMPH-treated group. Again, melatonin lowered this immunoreactivity. These results indicate that melatonin has a direct or indirect effect in reducing the expression of α-syn in the postnatal rat. The exact mechanism of this mitigation should be further investigated. © 2011 John Wiley & Sons A/S. Source


Itokawa M.,Tokyo Institute of Psychiatry | Arinami T.,University of Tsukuba | Toru M.,Tokyo Medical and Dental University
Journal of Pharmacological Sciences | Year: 2010

Schizophrenia is a debilitating and complex mental disorder with a prevalence of approximately 1% worldwide. The etiology remains unclear, despite massive research efforts. Hyperactive dopaminergic signal transduction in the central nervous system is suggested to be involved in the pathophysiology of schizophrenia (the dopamine hypothesis). The dopamine D2- receptor (DRD2) gene is thus a promising candidate for associations with risk of schizophrenia. We investigated DRD2 and found a novel missense nucleotide change causing an amino acid substitution of serine with cysteine at codon 311 (Ser311Cys). We performed an association study using 156 schizophrenia patients and 300 controls. Cys311 in DRD2 was significantly associated with schizophrenia. Patients with the Cys311 allele displayed shorter duration of hospitalization and less severe negative symptoms and were more frequently married compared to patients without this allele, suggesting good response to treatment. We expanded samples to 291 patients with schizophrenia (including 11 postmortem brain samples), 579 controls, and 78 patients with affective disorders in a further case-control study. Cys311 was associated with schizophrenia, particularly in patients without negative symptoms, and bipolar disorder with mood-incongruent psychotic symptoms. Three meta-analyses using over 20 published studies confirmed the association. In vitro studies showed that Cys311-type D2 receptor impairs dopamine-induced sequestration, which appears to be consistent with the dopamine hypothesis. ©2010 The Japanese Pharmacological Society. Source


It is essential to elucidate the relationship between blood oxygenation level-dependent (BOLD) signals and neuronal activity for the interpretation of the functional magnetic resonance imaging (fMRI) signals; this relationship has been quantitatively investigated by animal studies measuring evoked potentials as indices of neuronal activity. Although most human fMRI studies employ the event-related task design, in which the stimulus duration is short, few studies have investigated the relationship between BOLD signals and evoked potentials at short stimulus durations. The present study investigated this relationship in the somatosensory cortex of anesthetized rats by using electrical forepaw stimulation at a short duration of 4 s and comprehensively analyzed it at different frequencies (1-10 Hz) and currents (0.5-2.0 mA). Somatosensory evoked potential (SEP) responses were measured at the scalp using silver ball electrodes. The sum of the peak-to-peak amplitude (ΣSEP) and average SEP (avg. SEP) responses were calculated. BOLD signals were obtained using a spin-echo echo-planar imaging sequence at 7 T. The relationship between the avg. SEP and BOLD signals varied with frequency, whereas that between ΣSEP and BOLD signals showed a significant correlation at varying frequencies and currents. In particular, the relationship between ΣSEP and ΣBOLD, which is the sum of the BOLD signals obtained at each time point reflecting the area under the BOLD response curves, mostly converged, irrespective of the frequency. Our results suggest that ΣBOLD obtained using a spin-echo sequence reflects the neural activity as quantified by ΣSEP, which was determined at different frequencies and currents. © 2009 Elsevier B.V. All rights reserved. Source


Kobayashi T.,Niigata University | Washiyama K.,Niigata University | Ikeda K.,Tokyo Institute of Psychiatry
Neuropsychopharmacology | Year: 2010

Atomoxetine and reboxetine are commonly used as selective norepinephrine reuptake inhibitors (NRIs) for the treatment of attention-deficit/hyperactivity disorder and depression, respectively. Furthermore, recent studies have suggested that NRIs may be useful for the treatment of several other psychiatric disorders. However, the molecular mechanisms underlying the various effects of NRIs have not yet been sufficiently clarified. G-protein-activated inwardly rectifying K+ (GIRK or Kir3) channels have an important function in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to be a potential treatment for several neuropsychiatric disorders and cardiac arrhythmias. In this study, we investigated the effects of atomoxetine and reboxetine on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2, GIRK2, or GIRK1/GIRK4 subunits, extracellular application of atomoxetine or reboxetine reversibly reduced GIRK currents. The inhibitory effects were concentration-dependent, but voltage-independent, and time-independent during each voltage pulse. However, Kir1.1 and Kir2.1 channels were insensitive to atomoxetine and reboxetine. Atomoxetine and reboxetine also inhibited GIRK currents induced by activation of cloned A 1 adenosine receptors or by intracellularly applied GTPγS, a nonhydrolyzable GTP analogue. Furthermore, the GIRK currents induced by ethanol were concentration-dependently inhibited by extracellularly applied atomoxetine but not by intracellularly applied atomoxetine. The present results suggest that atomoxetine and reboxetine inhibit brain-and cardiac-type GIRK channels, revealing a novel characteristic of clinically used NRIs. GIRK channel inhibition may contribute to some of the therapeutic effects of NRIs and adverse side effects related to nervous system and heart function. © 2010 Nature Publishing Group All rights reserved. Source


Bandoh H.,Hokkaido University | Kida I.,Tokyo Institute of Psychiatry | Ueda H.,Hokkaido University
PLoS ONE | Year: 2011

Many studies have shown that juvenile salmon imprint olfactory memory of natal stream odors during downstream migration, and adults recall this stream-specific odor information to discriminate their natal stream during upstream migration for spawning. The odor information processing of the natal stream in the salmon brain, however, has not been clarified. We applied blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging to investigate the odor information processing of the natal stream in the olfactory bulb and telencephalon of lacustrine sockeye salmon (Oncorhynchus nerka). The strong responses to the natal stream water were mainly observed in the lateral area of dorsal telencephalon (Dl), which are homologous to the medial pallium (hippocampus) in terrestrial vertebrates. Although the concentration of L-serine (1 mM) in the control water was 20,000-times higher than that of total amino acid in the natal stream water (47.5 nM), the BOLD signals resulting from the natal stream water were stronger than those by L-serine in the Dl. We concluded that sockeye salmon could process the odor information of the natal stream by integrating information in the Dl area of the telencephalon. © 2011 Bandoh et al. Source

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