Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
Volume 99 , Issue 2
Showing 1-9 articles out of 9 articles from the selected issue
Current Perspective
  • Shigeo Kitayama, Chiharu Sogawa
    2005 Volume 99 Issue 2 Pages 121-127
    Published: 2005
    Released: October 18, 2005
    [Advance publication] Released: October 08, 2005
    JOURNALS FREE ACCESS
    Termination of neurotransmission at catecholaminergic synapses is well documented by the transporters for dopamine and norepinephrine, members of the Na+/Cl-dependent neurotransmitter transporter family, which accumulates released transmitters within their nerve endings, respectively. Although somatodendritic expression of the transporters and the effects of cocaine and amphetamine on those have been reported, their role is still obscure. Recent findings of the transporter function as an ion channel and/or its reverse transport property provide a clue to identify the role of these transporters in the somatodendrites and their consequential interaction with uptake inhibitors. Differences in ionic environment and maturity of the release machinery in the somatodendrites at developmental stages influence the transporter functions, resulting in the formation of both positive and negative feedback loop of catecholaminergic neurons.
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Critical Reviews
  • Akihiko Wada, Hiroki Yokoo, Toshihiko Yanagita, Hideyuki Kobayashi
    2005 Volume 99 Issue 2 Pages 128-143
    Published: 2005
    Released: October 18, 2005
    [Advance publication] Released: October 06, 2005
    JOURNALS FREE ACCESS
    Long after the pioneering studies documenting the existence of insulin (year 1967) and insulin receptor (year 1978) in brain, the last decade has witnessed extraordinary progress in the understanding of brain region-specific multiple roles of insulin receptor signalings in health and disease. In the hypothalamus, insulin regulates food intake, body weight, peripheral fat deposition, hepatic gluconeogenesis, reproductive endocrine axis, and compensatory secretion of counter-regulatory hormones to hypoglycemia. In the hippocampus, insulin promotes learning and memory, independent of the glucoregulatory effect of insulin. Defective insulin receptor signalings are associated with the dementia in normal aging and patients with age-related neurodegenerative diseases (e.g., Alzheimer’s disease); the cognitive impairment can be reversed with systemic administration of insulin in the euglycemic condition. Intranasal administration of insulin enhances memory and mood and decreases body weight in healthy humans, without causing hypoglycemia. In the hypothalamus, insulin-induced activation of the phosphoinositide 3-kinase pathway followed by opening of ATP-sensitive K+ channel has been shown to be related to multiple effects of insulin. However, the precise molecular mechanisms of insulin’s pleiotropic effects still remain obscure. More importantly, much remains unknown about the quality control mechanisms ensuring correct conformational maturation of the insulin receptor, and the cellular mechanisms regulating density of cell surface functional insulin receptors.
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  • Zhi-Bin Lin
    2005 Volume 99 Issue 2 Pages 144-153
    Published: 2005
    Released: October 18, 2005
    JOURNALS FREE ACCESS
    Ganoderma lucidum (Leyss. ex Fr.) Karst. (Lingzhi or Reishi) has been used for a long time in China to prevent and treat various human diseases. G. lucidum polysaccharides extracted from G. lucidum are one of efficacious ingredient groups of G. lucidum. A number of reports have demonstrated that G. lucidum polysaccharides modulate immune function both in vivo and in vitro. The immuno-modulating effects of G. lucidum polysaccharides were extensive, including promoting the function of antigen-presenting cells, mononuclear phygocyte system, humoral immunity, and cellular immunity. Cellular and molecular mechanisms, possible receptors involved, and triggered signaling cascades have also been studied in vitro. However, whole animal experiments are still needed to further establish the mechanism of the immuno-modulating effects by G. lucidum. Evidence-based clinical trials are also needed.
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Full Papers
  • Michihiko Matsushita, Nobuaki Egashira, Satoko Harada, Ryoko Okuno, Ke ...
    2005 Volume 99 Issue 2 Pages 154-159
    Published: 2005
    Released: October 18, 2005
    [Advance publication] Released: October 06, 2005
    JOURNALS FREE ACCESS
    Perospirone is a novel atypical antipsychotic drug with dopamine (DA) D2- and serotonin (5-hydroxytryptamine, 5-HT) 5-HT2A-receptor antagonist, and 5-HT1A-receptor agonist properties. In the present study, we examined the effect of perospirone on marble-burying behavior, which has been considered an animal model of obsessive-compulsive disorder (OCD), compared with the effects of other antipsychotics such as haloperidol and risperidone. Perospirone at a dose of 10 mg/kg (p.o.) inhibited marble-burying behavior without affecting the locomotor activity in mice. On the other hand, haloperidol (0.1 mg/kg, i.p.) and risperidone (1 mg/kg, p.o.) showed significant suppression of locomotor activity at the dose that inhibited marble-burying behavior. Furthermore, the inhibition of marble-burying behavior by perospirone was antagonized by WAY100135 (10 mg/kg, i.p.), a selective 5-HT1A-receptor antagonist. WAY100135 at the same dose also antagonized the inhibition of marble-burying behavior by 8-OH-DPAT (3 mg/kg, i.p.), a selective 5-HT1A-receptor agonist. These findings suggest that perospirone may exhibit anti-OCD activity in clinical use and that 5-HT1A-receptor agonistic activity may be involved in the inhibition of marble-burying behavior by perospirone.
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  • Chihiro Mogi, Hideaki Tomura, Masayuki Tobo, Ju-Qiang Wang, Alatangaol ...
    2005 Volume 99 Issue 2 Pages 160-167
    Published: 2005
    Released: October 18, 2005
    [Advance publication] Released: October 06, 2005
    JOURNALS FREE ACCESS
    Ovarian cancer G-protein-coupled receptor 1 (OGR1), previously proposed as a receptor for sphingosylphosphorylcholine (SPC), has recently been identified as a proton-sensing or extracellular pH-responsive G-protein-coupled receptor stimulating inositol phosphate production, reflecting the activation of phospholipase C. In the present study, we found that acidic pH stimulated cAMP accumulation, reflecting the activation of adenylyl cyclase, in addition to inositol phosphate production in OGR1-expressing cells. The cAMP response was hardly affected by the inhibition of phospholipase C. SPC inhibited the acidification-induced actions in a pH-dependent manner, while no OGR1-dependent agonistic action of SPC was observed. Thus, the dose-response curves of the proton-induced actions were shifted to the right in the presence of SPC regardless of stereoisoform. The antagonistic property was also observed for psychosine and glucosylsphingosine. In conclusion, OGR1 stimulation may lead to the activation of adenylyl cyclase in addition to phospholipase C in response to extracellular acidification but not to SPC. However, SPC and related lysolipids antagonize the proton-induced and OGR1-mediated actions.
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  • Mizuho Namiki, Tomohisa Mori, Toshiko Sawaguchi, Shinobu Ito, Tadashi ...
    2005 Volume 99 Issue 2 Pages 168-176
    Published: 2005
    Released: October 18, 2005
    [Advance publication] Released: October 06, 2005
    JOURNALS FREE ACCESS
    An increase in polydrug abuse is a major problem worldwide. A previous study showed that coadministration of methamphetamine and morphine induced lethality in rodents and humans. However, the underlying mechanisms by which the lethality is increased by the coadministration of methamphetamine and morphine have not been fully understood. Therefore, the present study was designed to determine the mechanism of increased lethality induced by methamphetamine and morphine. Coadministered methamphetamine and morphine increased the lethality by more than 70% in BALB/c mice. Pretreatment with NMDA-receptor antagonists, such as MK-801 and 3-((R)-2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP), and benzamide [poly(ADP-ribose) polymerase (PARP) inhibitor] significantly attenuated the increased lethality induced by methamphetamine and morphine. Furthermore, the lethal effect induced by methamphetamine and morphine was completely attenuated by immediate cooling after the coadministration of methamphetamine and morphine. It has been reported that methamphetamine-induced neurotoxicity can be blocked by lowering the temperature, and this effect might be mediated by a reduction of release of free radicals. These results suggest that activation of NMDA receptors and PARP play an important role in the increased lethality induced by methamphetamine and morphine.
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  • Hideki Suzuki, Nobuo Momoi, Tomoyuki Ono, Sachiko Maeda, Yayoi Shikama ...
    2005 Volume 99 Issue 2 Pages 177-184
    Published: 2005
    Released: October 18, 2005
    [Advance publication] Released: October 08, 2005
    JOURNALS FREE ACCESS
    Using the whole-cell voltage clamp technique, we investigated the effects of thiopental on membrane currents in H9c2 cells, a cell line derived from embryonic rat heart. Thiopental blocked a rapidly activating, very slowly-inactivating ultra-rapid type IKur-like outward K+ current in a concentration-dependent manner. The half-maximal concentration (IC50) of thiopental was 97 μM with a Hill coefficient of 1.2. The thiopental-sensitive current was also blocked by high concentrations of nifedipine (IC50 = 9.1 μM) and 100 μM chromanol 293B, a blocker of slowly activating delayed rectifier K+ current (IKs), but was insensitive to E-4031, an inhibitor of rapidly activating delayed rectifier K+ current (IKr). TEA (tetraethylammonium) at 5 mM and 4-AP (4-aminopiridine) at 1 mM reduced the K+ current to 30.8 ± 12.2% and 20.5 ± 6.5% of the control, respectively. Using RT-PCR, we detected mRNAs of Kv2.1, Kv3.4, Kv4.1, and Kv4.3 in H9c2 cells. Among those, Kv2.1 and Kv3.4 have IKur-type kinetics and are therefore candidates for thiopental-sensitive K+ channels in H9c2 cells. This is the first report showing that thiopental inhibits IKur. This effect of thiopental may be involved in its reported prolongation of cardiac action potentials.
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  • Yasue Sakaguchi, Atsushi Sugiyama, Shuji Takao, Yasuki Akie, Akira Tak ...
    2005 Volume 99 Issue 2 Pages 185-190
    Published: 2005
    Released: October 18, 2005
    [Advance publication] Released: October 08, 2005
    JOURNALS FREE ACCESS
    Potential utility of halothane-anesthetized guinea pigs for detecting drug-induced repolarization delay was analyzed in comparison with urethane-anesthesia (n = 4 for both groups). Basal QT interval was significantly greater under halothane-anesthesia than urethane-anesthesia (192 ± 7 vs 132 ± 5 ms, respectively), whereas the reverse was true for the heart rate (190 ± 7 vs 248 ± 11 beats/min, respectively). The typical IKr-blocker dl-sotalol (0.1 to 3 mg/kg, i.v.) induced dose-related bradycardia and QT interval prolongation under each anesthesia. The extent of maximum prolongation in the QT interval was greater under halothane-anesthesia than urethane-anesthesia (+101 ± 15 vs +49 ± 3 ms, respectively), whereas that of peak change in the heart rate was smaller under the former than the latter (−49 ± 8 vs −63 ± 5 beats/min, respectively). Pretreatment of the animals under urethane-anesthesia with the selective IKs blocker chromanol 293B (n = 6) increased the extent of the dl-sotalol-induced QT interval prolongation to +57 ± 8 ms, which was only 0.56 times of that under the halothane-anesthesia, whereas the pretreatment increased the peak change in the heart rate to −76 ± 12 ms. These results indicate that the halothane-anesthesia may effectively sensitize the guinea-pig heart to pharmacological IKr blockade.
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Short Communication
  • Keiji Tabuchi, Hidekazu Murashita, Tadamichi Tobita, Keiko Oikawa, Shi ...
    2005 Volume 99 Issue 2 Pages 191-194
    Published: 2005
    Released: October 18, 2005
    [Advance publication] Released: October 06, 2005
    JOURNALS FREE ACCESS
    The present study was performed to determine effects of dehydroepiandrosterone sulfate (DHEAS), a neurosteroid, on acoustic injury. Albino guinea pigs were exposed to a 2 kHz pure tone of 120 or 125 dB sound pressure level for 10 min immediately after intravenous administration of DHEAS. Statistically significant improvement in the compound action potential threshold shifts and in amplitude reduction of distortion-product otoacoustic emissions was observed 1 week after the acoustic overexposure in the animals treated with DHEAS. The present results suggest that DHEAS has a protective effect against acoustic injury of the cochlea.
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