Publications by authors named "Noriaki Koshikawa"

77 Publications

Oviposition in the onion fly (Diptera: Anthomyiidae) is socially facilitated by visual cues.

Bull Entomol Res 2020 Dec 15;110(6):677-683. Epub 2020 May 15.

Laboratory of Applied Entomology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.

Ovipositional decisions in herbivorous insects may be affected by social information from conspecifics. Social facilitation of oviposition has been suggested for the onion fly Delia antiqua. In the current study, we found that D. antiqua oviposition was unequal between paired oviposition stations of equal quality and that more eggs were laid on an oviposition station baited with decoy flies than on the control. The increased oviposition toward the decoys continued over time >8 h. When decoys were placed upside down, the number of eggs laid did not differ between the decoy and control sides of oviposition stations, suggesting that social facilitation of oviposition is mediated by visual cues. Based on these findings, mechanisms of social facilitation of oviposition in D. antiqua were discussed.
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http://dx.doi.org/10.1017/S0007485320000152DOI Listing
December 2020

Phase-dependent activity of neurons in the rostral part of the thalamic reticular nucleus with saccharin intake in a cue-guided lever-manipulation task.

Brain Res 2017 03 13;1658:42-50. Epub 2017 Jan 13.

Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan; Division of Oral and Craniomaxillofacial Research, Dental Research Center, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan; Molecular Dynamics Imaging Unit, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. Electronic address:

Neurons in the rostral part of the thalamic reticular nucleus (rTRN) receive somatosensory and motor information and regulate neural activities of the thalamic nuclei. Previous studies showed that when activity in visual TRN neurons is suppressed prior to the visual stimuli in a visual detection task, the performance of the task improves. However, little is known about such changes in the rTRN preceding certain events. In the present study, we performed unit recordings in the rTRN in alert rats during a cue-guided lever-manipulation task in which saccharin was provided as a reward. Changes in neural activity during saccharin intake were observed in 56% (51 of 91) of the recorded neurons; the firing rates increased in 21 neurons and decreased in 23 neurons. Seven neurons both increased and decreased their firing rates during saccharin intake. Changes in firing rates during the reward-waiting stage between task termination and saccharin intake were also observed in 73% (37 of 51) of the neurons that responded to saccharin intake. Increased activity during saccharin intake did not correlate with increased activity during lever-manipulation or activity during the reward-waiting stage. However, decreased activity during saccharin intake was correlated with activity during the reward-waiting stage. These results suggest that rTRN neurons have phase-dependent changes in their activity and regulate the thalamic activities. Furthermore, the decreased activity of rTRN neurons before reward may contribute to refine somatosensory and motor information processing in the thalamic nuclei depending on the status of mind such as expectation and attention.
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http://dx.doi.org/10.1016/j.brainres.2017.01.013DOI Listing
March 2017

Spike Timing Rigidity Is Maintained in Bursting Neurons under Pentobarbital-Induced Anesthetic Conditions.

Front Neural Circuits 2016 14;10:86. Epub 2016 Nov 14.

Department of Pharmacology, School of Dentistry, Nihon UniversityChiyoda, Japan; Division of Oral and Craniomaxillofacial Research, Dental Research Center, School of Dentistry, Nihon UniversityChiyoda, Japan; Molecular Dynamics Imaging Unit, RIKEN Center for Life Science TechnologiesKobe, Japan.

Pentobarbital potentiates γ-aminobutyric acid (GABA)-mediated inhibitory synaptic transmission by prolonging the open time of GABA receptors. However, it is unknown how pentobarbital regulates cortical neuronal activities via local circuits . To examine this question, we performed extracellular unit recording in rat insular cortex under awake and anesthetic conditions. Not a few studies apply time-rescaling theorem to detect the features of repetitive spike firing. Similar to these methods, we define an average spike interval locally in time using random matrix theory (RMT), which enables us to compare different activity states on a universal scale. Neurons with high spontaneous firing frequency (>5 Hz) and bursting were classified as HFB neurons ( = 10), and those with low spontaneous firing frequency (<10 Hz) and without bursting were classified as non-HFB neurons ( = 48). Pentobarbital injection (30 mg/kg) reduced firing frequency in all HFB neurons and in 78% of non-HFB neurons. RMT analysis demonstrated that pentobarbital increased in the number of neurons with repulsion in both HFB and non-HFB neurons, suggesting that there is a correlation between spikes within a short interspike interval (ISI). Under awake conditions, in 50% of HFB and 40% of non-HFB neurons, the decay phase of normalized histograms of spontaneous firing were fitted to an exponential function, which indicated that the first spike had no correlation with subsequent spikes. In contrast, under pentobarbital-induced anesthesia conditions, the number of non-HFB neurons that were fitted to an exponential function increased to 80%, but almost no change in HFB neurons was observed. These results suggest that under both awake and pentobarbital-induced anesthetized conditions, spike firing in HFB neurons is more robustly regulated by preceding spikes than by non-HFB neurons, which may reflect the GABA receptor-mediated regulation of cortical activities. Whole-cell patch-clamp recording in the IC slice preparation was performed to compare the regularity of spike timing between pyramidal and fast-spiking (FS) neurons, which presumably correspond to non-HFB and HFB neurons, respectively. Repetitive spike firing of FS neurons exhibited a lower variance of ISI than pyramidal neurons both in control and under application of pentobarbital, supporting the above hypothesis.
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http://dx.doi.org/10.3389/fncir.2016.00086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107820PMC
October 2017

Opioid subtype- and cell-type-dependent regulation of inhibitory synaptic transmission in the rat insular cortex.

Neuroscience 2016 Dec 8;339:478-490. Epub 2016 Oct 8.

Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan; Division of Oral and Craniomaxillofacial Research, Dental Research Center, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan; RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan. Electronic address:

The insular cortex (IC) plays a principal role in the regulation of pain processing. Although opioidergic agonists depress cortical excitatory synaptic transmission, little is known about opioidergic roles in inhibitory synaptic transmission. In the IC, the opioid receptors differentially regulate the excitatory propagation: agonists of the mu (MOR), delta (DOR), and kappa (KOR) exhibit suppressive, facilitative, and little effects, respectively. Thus, we aimed to examine the effects of opioid receptor agonists on unitary inhibitory postsynaptic currents (uIPSCs) in the IC. Pyramidal and GABAergic neurons in the rat IC were recorded by a multiple whole-cell patch-clamp technique. [D-Ala,N-Me-Phe,Gly-ol]-Enkephalin acetate salt (DAMGO), an MOR agonist, reduced uIPSC amplitude by 74% in fast-spiking GABAergic interneuron (FS)→FS connections without a significant effect on FS→pyramidal cell (Pyr) connections. These effects of DAMGO were also observed in non-FS→FS and non-FS→Pyr connections: DAMGO reduced the uIPSC amplitude in non-FS→FS but not in non-FS→Pyr connections. DAMGO-induced depression of uIPSCs was blocked by the MOR antagonist, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH. The DOR agonist, [D-Pen]-Enkephalin hydrate (DPDPE), reduced uIPSC amplitude by 39% in FS→FS and by 49% in FS→Pyr connections, which was antagonized by the DOR antagonist, naltrindole. However, DPDPE had little effect on non-FS→FS/Pyr connections. (±)-trans-U-50488 methanesulfonate salt (U50488), a KOR agonist, had little effect on uIPSC in FS→FS/Pyr connections. These results suggest that MOR-induced uIPSC depression in FS→FS and non-FS→FS, but not FS→Pyr and non-FS→Pyr connections, results in the depression of excitatory propagation in the IC, which may be an underlying mechanism of the powerful analgesic effects of MOR agonists.
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http://dx.doi.org/10.1016/j.neuroscience.2016.10.004DOI Listing
December 2016

Cytoarchitecture-Dependent Decrease in Propagation Velocity of Cortical Spreading Depression in the Rat Insular Cortex Revealed by Optical Imaging.

Cereb Cortex 2016 Apr 16;26(4):1580-1589. Epub 2015 Jan 16.

Department of Pharmacology, Dental Research Center, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.

Cortical spreading depression (SD) is a self-propagating wave of depolarization accompanied by a substantial disturbance of the ionic distribution between the intra- and extracellular compartments. Glial cells, including astrocytes, play critical roles in maintenance of the extracellular environment, including ionic distribution. Therefore, SD propagation in the cerebral cortex may depend on the density of astrocytes. The present study aimed to examine the profile of SD propagation in the insular cortex (IC), which is located between the neocortex and paleocortex and is where the density of astrocytes gradually changes. The velocity of SD propagation in the neocortex, including the somatosensory, motor, and granular insular cortices (5.7 mm/min), was higher than that (2.8 mm/min) in the paleocortex (agranular insular and piriform cortices). Around thick vessels, including the middle cerebral artery, SD propagation was frequently delayed and sometimes disappeared. Immunohistological analysis of glial fibrillary acidic protein (GFAP) demonstrated the sparse distribution of astrocytes in the somatosensory cortex and the IC dorsal to the rhinal fissure, whereas the ventral IC showed a higher density of astrocytes. These results suggest that cortical cytoarchitectonic features, which possibly involve the distribution of astrocytes, are crucial for regulating the velocity of SD propagation in the cerebral cortex.
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http://dx.doi.org/10.1093/cercor/bhu336DOI Listing
April 2016

Investigating complex basal ganglia circuitry in the regulation of motor behaviour, with particular focus on orofacial movement.

Behav Pharmacol 2015 Feb;26(1-2):18-32

aDepartment of Pharmacology, Nihon University School of Dentistry bDepartment of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo cDepartment of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, Saitama dDepartment of Pharmacology, Nihon University School of Dentistry at Matsudo, Chiba, Japan eMolecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.

Current concepts of basal ganglia function have evolved from the essentially motoric, to include a range of extramotoric functions that involve not only dopaminergic but also cholinergic, γ-aminobutyric acid (GABA)ergic and glutamatergic mechanisms. We consider these mechanisms and their efferent systems, including spiralling, feed-forward striato-nigro-striatal circuitry, involving the dorsal and ventral striatum and the nucleus accumbens (NAc) core and shell. These processes are illustrated using three behavioural models: turning-pivoting, orofacial movements in rats and orofacial movements in genetically modified mice. Turning-pivoting indicates that dopamine-dependent behaviour elicited from the NAc shell is funnelled through the NAc-nigro-striato-nigro-pedunculopontine pathway, whereas acetylcholine-dependent behaviour elicited from the NAc shell is funnelled through the NAc-ventral pallidum-mediodorsal thalamus pathway. Cooperative/synergistic interactions between striatal D1-like and D2-like dopamine receptors regulate individual topographies of orofacial movements that are funnelled through striatal projection pathways and involve interactions with GABAergic and glutamatergic receptor subtypes. This application of concerted behavioural, neurochemical and neurophysiological techniques implicates a network that is yet broader and interacts with other neurotransmitters and neuropeptides within subcortical, cortical and brainstem regions to 'sculpt' aspects of behaviour into its topographical collective.
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http://dx.doi.org/10.1097/FBP.0000000000000118DOI Listing
February 2015

Simultaneous activation of the α1A-, α1B- and α1D-adrenoceptor subtypes in the nucleus accumbens reduces accumbal dopamine efflux in freely moving rats.

Behav Pharmacol 2015 Feb;26(1-2):73-80

aDepartment of Pharmacology, Nihon University School of Dentistry at Matsudo, Chiba Departments of bPharmacology cOrthodontics dAnaesthesiology ePediatric Dentistry fDivision of Oral and Craniomaxillofacial Research, Dental Research Centre, Nihon University School of Dentistry, Tokyo, Japan gDepartment of Cognitive Neuroscience, Radboud University Medical Centre Nijmegen, Division of Psychoneuropharmacology, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, The Netherlands.

Intra-accumbal infusion of the α1-adrenergic agonist methoxamine, which has comparable affinity for α1A-, α1B- and α1D-adrenoceptor subtypes, fails to alter noradrenaline efflux but reduces dopamine efflux in the nucleus accumbens of rats. In-vivo microdialysis experiments were carried out to analyse the putative contribution of α1A-, α1B- and α1D-adrenoceptor subtypes to the methoxamine-induced decrease in accumbal dopamine efflux in freely moving rats. The drugs used were dissolved in the infusion medium and administered locally through a dialysis membrane. Intra-accumbal infusions of the α1A-adrenoceptor antagonist 5-methylurapidil (6 pmol), the α1B-adrenoceptor antagonist cyclazosin (0.6 and 6 pmol) and the α1D-adrenoceptor antagonist BMY 7378 (0.6 pmol) did not alter accumbal efflux of noradrenaline or dopamine: pretreatment with each of these α1-adrenoceptor subtype-selective antagonists counteracted the methoxamine (24 pmol)-induced decrease in accumbal dopamine efflux. Doses indicated are the total amount of drug administered over a 60-min infusion period. These results clearly suggest that the α1A-, α1B- and α1D-adrenoceptor subtypes in the nucleus accumbens mediate the α1-adrenergic agonist methoxamine-induced decrease in accumbal dopamine efflux. The present study also provides in-vivo neurochemical evidence indicating that concomitant, but not separate, activation of the α1A-, α1B- and α1D-adrenoceptors in the nucleus accumbens is required for α1-adrenergic inhibition of accumbal dopaminergic activity.
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http://dx.doi.org/10.1097/FBP.0000000000000113DOI Listing
February 2015

Accumbal α-adrenoceptors, but not β-adrenoceptors, regulate behaviour that is mediated by reserpine-sensitive storage vesicles.

Behav Pharmacol 2015 Feb;26(1-2):81-90

aDepartment of Cognitive Neuroscience (CNS), Radboud University Nijmegen Medical Centre, Division of Psychoneuropharmacology, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands bDepartment of Pharmacology, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba cDepartment of Pharmacology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo, Japan.

It has previously been demonstrated that mesolimbic α-adrenoceptors, but not β-adrenoceptors, control the release of dopamine that is derived from reserpine-sensitive storage vesicles. The aim of the present study was to investigate whether these storage vesicles also regulate α-adrenoceptor-mediated or β-adrenoceptor-mediated changes in behaviour. Accordingly, rats were pretreated with reserpine before the α-adrenoceptor antagonist phentolamine or the β-adrenoceptor agonist isoproterenol was locally applied to the nucleus accumbens. Both phentolamine and isoproterenol increased the duration of walking, rearing and grooming and decreased the duration of sitting. Reserpine counteracted the behavioural response elicited by phentolamine but not by isoproterenol. The results of the present study demonstrate that mesolimbic α-adrenoceptors, but not β-adrenoceptors, regulate behaviour that is mediated by reserpine-sensitive storage pools. It is hypothesized that the observed α-adrenoceptor-mediated increase in locomotor activity is due to the α-adrenoceptor-mediated increase in the release of accumbal intravesicular dopamine. Our finding that α-adrenoceptors inhibit, whereas β-adrenoceptors stimulate, locomotor activity may help explain why noradrenaline or environmental stressors have previously been found to have opposing effects on the regulation of behaviour.
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http://dx.doi.org/10.1097/FBP.0000000000000098DOI Listing
February 2015

Spatiotemporal profiles of dental pulp nociception in rat cerebral cortex: an optical imaging study.

J Comp Neurol 2015 Jun 16;523(8):1162-74. Epub 2015 Mar 16.

Department of Pharmacology, Nihon University School of Dentistry, Tokyo, 101-8310, Japan; Department of Pediatric Dentistry, Nihon University School of Dentistry, Tokyo, 101-8310, Japan.

Somatosensation is topographically organized in the primary (S1) and secondary somatosensory cortex (S2), which contributes to identify the region receiving sensory inputs. However, it is still unknown how somatosensory inputs from the oral region, especially nociceptive inputs from the teeth, are processed in the somatosensory cortex. We performed in vivo optical imaging and identified the precise cortical regions responding to electrical stimulation of the maxillary and mandibular dental pulp in rats. Electrical stimulation of the mandibular incisor pulp evoked neural excitation in two areas: the most rostroventral part of S1, and the ventral part of S2 caudal to the middle cerebral artery. Maxillary incisor pulp stimulation initially evoked responses only in the ventral part of S2, although later maximum responses were also observed in S1 similar to mandibular incisor stimulation responses. The maxillary and mandibular molar pulp-responding regions were located in the most ventral S2, a part of which was histologically classified as the insular oral region (IOR). In terms of the initial responses, maxillary incisor and molar stimulation induced excitation in the S2/IOR rostral to the mandibular dental pulp-responding region. Contrary to the spatially segregated initial responses, the maximum excitatory areas responding to both incisors and molars in the mandible and maxilla overlapped in S1 and the S2/IOR. Multielectrode extracellular recording supported the characteristic localization of S2/IOR neurons responding to mandibular and maxillary molar pulp stimulation. The discrete and overlapped spatial profiles of initial and maximum responses, respectively, may characterize nociceptive information processing of dental pain in the cortex.
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http://dx.doi.org/10.1002/cne.23692DOI Listing
June 2015

Fast-spiking cell to pyramidal cell connections are the most sensitive to propofol-induced facilitation of GABAergic currents in rat insular cortex.

Anesthesiology 2014 Jul;121(1):68-78

From the Department of Anesthesiology (Y.K., Y.O.), and Department of Pharmacology (K.Y., N.K., M.K.), Nihon University School of Dentistry, Tokyo, Japan; Division of Immunology and Pathobiology (Y.K., Y.O.), and Division of Oral and Craniomaxillofacial Research (K.Y., N.K., M.K.), Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan; and Molecular Dynamics Imaging Unit, RIKEN Center for Life Science Technologies, Kobe, Japan (M.K.).

Background: Propofol facilitates γ-aminobutyric acid-mediated inhibitory synaptic transmission. In the cerebral cortex, γ-aminobutyric acidergic interneurons target both excitatory pyramidal cells (Pyr) and fast-spiking (FS) and non-FS interneurons. Therefore, the propofol-induced facilitation of inhibitory transmission results in a change in the balance of excitatory and inhibitory inputs to Pyr. However, it is still unknown how propofol modulates γ-aminobutyric acidergic synaptic transmission in each combination of Pyr and interneurons.

Methods: The authors examined whether propofol differentially regulates inhibitory postsynaptic currents (IPSCs) depending on the presynaptic and postsynaptic cell subtypes using multiple whole cell patch clamp recording from γ-aminobutyric acidergic interneurons and Pyr in rat insular cortex.

Results: Propofol (10 μM) consistently prolonged decay kinetics of unitary IPSCs (uIPSCs) in all types of inhibitory connections without changing paired-pulse ratio of the second to first uIPSC amplitude or failure rate. The FS→Pyr connections exhibited greater enhancement of uIPSC charge transfer (2.2 ± 0.5 pC, n = 36) compared with that of FS→FS/non-FS connections (0.9 ± 0.2 pC, n = 37), whereas the enhancement of charge transfer in non-FS→Pyr (0.3 ± 0.1 pC, n = 15) and non-FS→FS/non-FS connections (0.2 ± 0.1 pC, n = 36) was smaller to those in FS→Pyr/FS/non-FS. Electrical synapses between FS pairs were not affected by propofol.

Conclusions: The principal inhibitory connections (FS→Pyr) are the most sensitive to propofol-induced facilitation of uIPSCs, which is likely mediated by postsynaptic mechanisms. This preferential uIPSC enhancement in FS→Pyr connections may result in suppressed neural activities of projection neurons, which in turn reduces excitatory outputs from cortical local circuits.
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http://dx.doi.org/10.1097/ALN.0000000000000183DOI Listing
July 2014

Reciprocal regulation of inhibitory synaptic transmission by nicotinic and muscarinic receptors in rat nucleus accumbens shell.

J Physiol 2013 Nov 9;591(22):5745-63. Epub 2013 Sep 9.

M. Kobayashi: Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.

Medium spiny neurones (MSNs) in the nucleus accumbens (NAc) are the principal neurones whose activities are regulated by GABAergic inputs from MSNs and fast-spiking interneurones (FSNs). Cholinergic interneurones play important roles in the regulation of activity in MSNs; however, how acetylcholine modulates inhibitory synaptic transmission from MSNs/FSNs to MSNs remains unknown. We performed paired whole-cell patch-clamp recordings from MSNs and FSNs in rat NAc shell slice preparations and examined cholinergic effects on unitary inhibitory postsynaptic currents (uIPSCs). Carbachol (1 μM) suppressed uIPSC amplitude by 58.3 ± 8.0% in MSN→MSN connections, accompanied by increases in paired-pulse ratio and failure rate, suggesting that acetylcholine reduces the probability of GABA release from the synaptic terminals of MSNs. Carbachol-induced uIPSC suppression was antagonised by 100 μM atropine, and was mimicked by pilocarpine (1 μM) and acetylcholine (1 μM) but not nicotine (1 μM). Application of AM251 slightly reduced carbachol-induced uIPSC suppression (30.8 ± 8.9%), suggesting an involvement of endocannabinoid signalling in muscarinic suppression of uIPSCs. In contrast, FSN→MSN connections showed that pilocarpine had little effect on the uIPSC amplitude, whereas both nicotine and acetylcholine facilitated uIPSC amplitude, with decreases in failure rate and paired-pulse ratio, suggesting that nicotine-induced uIPSC facilitation is mediated by presynaptic mechanisms. Miniature IPSC recordings support these hypotheses of presynaptic cholinergic mechanisms. These results suggest a differential role for muscarinic and nicotinic receptors in GABA release, which depends on presynaptic neuronal subtypes in the NAc shell.
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http://dx.doi.org/10.1113/jphysiol.2013.258558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853507PMC
November 2013

Functional neuroimaging of aversive taste-related areas in the alert rat revealed by positron emission tomography.

J Neurosci Res 2013 Oct 30;91(10):1363-70. Epub 2013 Jul 30.

Department of Pharmacology, Nihon University School of Dentistry, Tokyo, Japan; Division of Oral and Craniomaxillofacial Research, Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan; RIKEN Center for Molecular Imaging Science, Kobe, Japan.

Among noninvasive functional brain imaging techniques, (18) F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) has a comparative advantage in detecting active brain regions in freely locomoting animals. We developed an [(18) F]FDG-PET protocol that visualizes active brain regions that respond preferentially to citrate-induced multiple behaviors in freely locomoting rats. In addition, c-Fos immunohistochemistry, an activity-dependent mapping, was performed to examine whether the areas detected by PET correspond to regions with c-Fos-immunopositive neurons. Citrate (0.1 M) was intraorally applied to detect activated brain regions responding to gustation and the rejection behaviors including gaping and tongue protrusion, which would potently activate the limbic system. PET images during citrate stimulation were subtracted from those obtained during free locomotion or during application of distilled water. Citrate increased FDG signals in multiple gustation-related regions: the nucleus accumbens (core and shell), the ventromedial nucleus of the thalamus, the basolateral and central nuclei of the amygdala, the hypothalamus, and the insular cortex. In addition, the ventrolateral striatum and the cingulate and entorhinal cortices, which have received less attention in the field of gustatory studies, also showed an increase in FDG signals. As expected, c-Fos-immunopositive cells were also found in these regions, suggesting that increased FDG signals induced by intraoral citrate injection are likely to reflect neural activity in these regions. Our [(18) F]FDG-PET protocol reveals the contributions of multiple brain regions responding to aversive taste in freely locomoting rats, and this approach may aid in the identification of unknown neural networks especially relating to the limbic information processing.
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http://dx.doi.org/10.1002/jnr.23252DOI Listing
October 2013

Synergistic, but not separate, stimulation of accumbal β1- and β2-adrenoceptors alters the accumbal dopamine efflux in freely moving rats.

Eur J Pharmacol 2013 Sep 9;715(1-3):363-9. Epub 2013 May 9.

Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.

The effects of intra-accumbal infusion of selective agonists for the β-adrenoceptor subtypes on the noradrenaline and dopamine efflux in the nucleus accumbens of freely moving rats were investigated, using in vivo microdialysis. Neither β1-(dobutamine: 0.06 and 0.12 pmol) nor β2-adrenoceptor agonist (salbutamol: 0.36 and 3.6 pmol) altered the basal noradrenaline and dopamine efflux in the nucleus accumbens. Co-administration of 0.06 pmol of dobutamine with salbutamol (3.6 pmol) did not affect the noradrenaline levels, but it increased the dopamine efflux to approximately 120%. Co-administration of 0.12 pmol of dobutamine with salbutamol (0.36 or 3.6pmol) also increased DA efflux to approximately 120% without affecting noradrenaline levels. The non-selective β-adrenoceptor antagonist l-propranolol (1200 pmol) that did not alter the basal noradrenaline and dopamine levels, suppressed the dopamine efflux, induced by co-administration of dobutamine (0.12 pmol) and salbutamol (3.6 pmol). The doses mentioned are the total amount of drug over the 60-min infusion period. The present results support our previously reported conclusion that stimulation of accumbal β-adrenoceptors which are suggested to be postsynaptically located on accumbal dopaminergic terminals, can enhance the dopamine efflux in the nucleus accumbens. The present study also provides in vivo neurochemical evidence that concomitant, but not separate, activation of accumbal β1- and β2-adrenoceptors synergistically increases the accumbal dopamine efflux.
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http://dx.doi.org/10.1016/j.ejphar.2013.04.035DOI Listing
September 2013

Apomorphine-induced modulation of neural activities in the ventrolateral striatum of rats.

Synapse 2013 Jul 7;67(7):363-73. Epub 2013 Mar 7.

Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-8310, Japan.

The dopaminergic system in the ventrolateral portion of the striatum (Svl), part of the basal ganglia, regulates orofacial movements; bilateral co-stimulation of both dopamine D1 -like and D2 -like receptors elicits repetitive jaw movements in rats. However, how the activities of Svl neurons are modulated by the activation of dopaminergic receptors remains unknown. We systematically injected apomorphine, a non-selective dopamine receptor agonist that induced jaw movements under urethane anesthesia, and performed multi-channel unit recording from Svl neurons. The Svl neurons were classified into two subgroups: (1) the phasically active (PA) neurons represented by mainly the medium spiny neurons and the GABAergic interneurons in part, and (2) the tonically active (TA) neurons composed of mainly the cholinergic interneurons. Apomorphine modulated PA neuron firing frequency with wide variability; 33.3% of the PA neurons were facilitated, while 38.3% were suppressed. In the majority of TA neurons, the firing frequency was reduced by apomorphine (71.1%). The cross-correlations between PA and PA, PA and TA, and TA and TA neurons were analyzed, and pairs of PA neurons and pairs of PA and TA neurons, showed negligible apomorphine-induced effect on the number of synchronized spikes. In contrast, pairs between TA neurons showed a consistent decrease in the number of synchronized spikes. The apomorphine-induced suppression of TA neuron activities with decreased synchronized outputs is likely to reduce the amount of locally released acetylcholine, which may contribute to the induction of apomorphine-induced jaw movements in rats.
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http://dx.doi.org/10.1002/syn.21644DOI Listing
July 2013

Anatomical and electrophysiological mechanisms for asymmetrical excitatory propagation in the rat insular cortex: in vivo optical imaging and whole-cell patch-clamp studies.

J Comp Neurol 2013 May;521(7):1598-613

Division of Pharmacology, Meikai University School of Dentistry, Saitama 350-0283, Japan.

The insular cortex (IC) integrates limbic information from the amygdala and hypothalamic nucleus to multimodal sensory inputs, including visceral, gustatory, and somatosensory information. However, the functional framework of excitation in the IC is still unknown. We performed optical imaging and single pyramidal neuronal staining using a whole-cell patch-clamp technique in urethane-anesthetized rats to elucidate the precise anatomical and physiological features of IC pyramidal neurons, which regulate cortical information processing via their horizontal connections. Optical imaging revealed that electrical stimulation of the granular (GI) or dysgranular (DI) IC elicited characteristic excitatory propagations along the rostrocaudal axis parallel to the rhinal fissure, with a preference toward the rostral direction. Spatial patterns of the dendrites and axons of layer II/III pyramidal cells in the DI/GI support these functional features of excitation; for example, rostrocaudal axonal arbors tend to extend with a rostral directional preference. The mean length of the axons from the soma to the farthest site rostrally was ∼50% longer than that of the caudal length. Pyramidal cells in the DI/GI exhibited spontaneous membrane oscillation in the UP and DOWN states. Similarly to the evoked signals obtained by optical imaging, repetitive electrical stimulation of the caudal IC ∼1 mm away from the recorded cells (five pulses at 50 Hz) induced the summation of evoked excitatory postsynaptic potentials during the DOWN state and profound inhibitory postsynaptic potentials during the UP state. Clarification of the excitation feature with its cellular basis provides new clues about the functional mechanisms of the asymmetric propagation of neural activities in the IC.
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http://dx.doi.org/10.1002/cne.23246DOI Listing
May 2013

Nucleus accumbens and dopamine-mediated turning behavior of the rat: role of accumbal non-dopaminergic receptors.

J Pharmacol Sci 2012 10;120(3):152-64. Epub 2012 Oct 10.

Department of Pharmacology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo, Japan.

Accumbal dopamine plays an important role in physiological responses and diseases such as schizophrenia, Parkinson's disease, and depression. Since the nucleus accumbens contains different neurotransmitters, it is important to know how they interact with dopaminergic function: this is because modifying accumbal dopamine has far-reaching consequences for the treatment of diseases in which accumbal dopamine is involved. This review provides a summary of these interactions, and our current knowledge about them are as follows: A) AMPA receptors are required for dopamine-dependent behavior and vice versa; NMDA receptors modulate the activity at the level of AMPA and/or dopamine D₁ receptors. B) GABA(A), but not GABA(B), receptors inhibit dopamine-dependent behavior. C) Nicotinic receptors are required for dopamine-dependent behavior, whereas muscarinic receptors inhibit dopamine-dependent behavior. D) α-Adrenoceptors inhibit dopamine-dependent behavior in contrast to β-adrenoceptors, which potentiate this behavior. E) μ- and δ₂-opioid receptors elicit behavior that requires an intact dopaminergic function and δ₂-opioid receptors modulate dopamine-dependent behavior. F) Orexin 2 receptors play an important, modifying role in dopamine-dependent behavior. G) Somatostatin receptors potentiate dopamine-dependent behavior. It is suggested that modulation of the above-mentioned non-dopaminergic receptors provide new tools to control physiological functions as well as diseases mediated by accumbal dopamine.
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http://dx.doi.org/10.1254/jphs.12r02crDOI Listing
April 2013

Constitutive and conditional mutant mouse models for understanding dopaminergic regulation of orofacial movements: emerging insights and challenges.

J Pharmacol Sci 2012 21;119(4):297-301. Epub 2012 Jul 21.

Advanced Research Institute for the Sciences and Humanities, Nihon University, Japan.

Among numerous mechanisms implicated in the regulation of orofacial movements, dopamine-containing neurons have received the most extensive study. Here we review the effects of a) constitutive knockout of D(1-5) dopamine receptors and b) conditional mutations with progressive ablation of D(1) receptor-expressing cells, on the topography of spontaneous and D(1)-like agonist-induced orofacial movements. In constitutive knockouts, D(1) and D(2) exert primary roles in regulating horizontal and vertical jaw movements, respectively, in opposite directions; in contrast, both D(1) and D(2) receptors regulate tongue protrusions and incisor chattering, in the same direction. D(3) and D(5) receptors play more subtle roles in regulating orofacial movements, while D(4) receptors do not play any material role. Progressive loss of forebrain D(1) receptor-expressing cells in CamKIIa/Cre D(1)Tox mutants is associated primarily with decreases in head and vibrissae movements, while progressive loss of striatal D(1) receptor-expressing cells in DARPP-32/Cre D(1)Tox mutants is associated primarily with reductions in jaw movements and tongue protrusions but increases in head and vibrissae movements. Further application of constitutive and particularly conditional mutants may clarify further not only dopaminergic regulation of orofacial movements but also the pathophysiology of orofacial dysfunction in Huntington's disease and Parkinson's disease.
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http://dx.doi.org/10.1254/jphs.12r05cpDOI Listing
January 2013

The α₁-, but not α₂-, adrenoceptor in the nucleus accumbens plays an inhibitory role upon the accumbal noradrenaline and dopamine efflux of freely moving rats.

Eur J Pharmacol 2012 Aug 19;688(1-3):35-41. Epub 2012 May 19.

Department of Pharmacology, Nihon University School of Dentistry, 1-8-13, Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.

In vivo microdialysis was used to analyse the role of the α(1)- and α(2)-adrenoceptor subtypes in the regulation of noradrenaline and dopamine efflux in the nucleus accumbens of freely moving rats. Intra-accumbal infusion of α(1)-adrenoceptor agonist methoxamine (24pmol) failed to alter the noradrenaline efflux, but decreased the dopamine efflux. The intra-accumbal infusion of α(1)-adrenoceptor antagonist prazosin (6, 600 and 6000pmol) produced a dose-related increase and decrease of the noradrenaline and dopamine efflux, respectively. An ineffective dose of prazosin (6pmol) counteracted the methoxamine (24pmol)-induced decrease of dopamine efflux. The prazosin (6000pmol)-induced increase of noradrenaline efflux, but not the decrease of dopamine efflux, was suppressed by the co-administration of an ineffective dose of methoxamine (0.024pmol). Neither the α(2)-adrenoceptor agonist clonidine (300pmol) and UK 14,304 (300pmol) nor the α(2)-adrenoceptor antagonist RX 821002 (0.6, 3, 600 and 6000pmol) significantly affected the accumbal noradrenaline and dopamine efflux. The doses mentioned are the total amount of drug over the 60-min infusion period. The present results show that (1) accumbal α(1)-adrenoceptors which are presynaptically located on noradrenergic nerve terminals inhibit the accumbal noradrenaline efflux, increasing thereby the accumbal dopamine efflux, (2) accumbal α(1)-adrenoceptors which are postsynaptically located on dopaminergic nerve terminals inhibit the accumbal dopamine efflux, and (3) accumbal α(2)-adrenoceptors play no major role in the regulation of accumbal efflux of noradrenaline and dopamine.
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http://dx.doi.org/10.1016/j.ejphar.2012.05.005DOI Listing
August 2012

Histaminergic effects on the frequency of repetitive spike firing in rat insular cortex.

Neurosci Lett 2012 Jun 2;518(1):55-9. Epub 2012 May 2.

Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Tokyo 101-8310, Japan.

The insular cortex (IC) processes multimodal sensory information including gustatory, visceral, nociceptive, and thermal sensation, and is considered to play a role in the regulation of homeostasis. The IC receives dense histaminergic projection from the tuberomamillary nucleus in the hypothalamus, and recent studies have demonstrated that the blockage of histaminergic receptors impairs physiological functions in the IC. However, little is known about the effects of histamine on the electrophysiological properties of the IC. To explore the effects of histamine on the subthreshold responses and action potential properties in the IC, intracellular recording with a sharp glass electrode was obtained from IC pyramidal cells in cortical slice preparations. Application of histamine (30 μM) increased the frequency of repetitive spike firing in response to a long depolarizing current pulse injection; accompanied by an increase in input resistance. The frequency of repetitive spike firing was estimated by the slope of the frequency-current (f/I) curve. Histamine caused an increase from 23.3±2.3 Hz/nA to 40.3±4.3 Hz/nA. The histamine-induced facilitation of repetitive spike firing was blocked by pre-application of 50 μM cimetidine, an H(2) receptor antagonist, but not 30 μM pyrilamine, an H(1) receptor antagonist. R-α-methylhistamine (10 μM), an H(3) autoreceptor agonist, had little effect on the slope of the f/I curve. These results suggest that the histamine-induced facilitation of firing frequency is mediated via H(2) and not H(1) receptors. In addition, H(3) receptors have a minor role in the intrinsic membrane and firing properties of IC pyramidal cells.
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http://dx.doi.org/10.1016/j.neulet.2012.04.056DOI Listing
June 2012

Disruption of programmed masticatory movements in unilateral MPTP-treated monkeys as a model of jaw movement abnormality in Parkinson's disease.

J Neural Transm (Vienna) 2012 Aug 17;119(8):933-41. Epub 2012 Feb 17.

Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo, Japan.

While motor disturbance in Parkinson's disease can affect innate, programmed processes, such as masticatory mandibular movements, the pathophysiology of such abnormalities remains unclear. This study applies digital analysis by high-speed video signal processing that tracks three dots placed around the mouth for recording masticatory movements in unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. The system analyzes displacement, velocity and cycle duration of the topography of mandibular movement during mastication of sweet potato slices. In monkeys receiving MPTP into the right carotid artery (n = 3), positron emission tomography indicated significant reduction in the binding of (E)-N-(3-iodoprop-2-enyl)-2β-carbo[(11)C]methoxy-3β-(4-methylphenyl)nortropane ([(11)C]PE2I) to the dopamine transporter in the right caudate, putamen, nucleus accumbens and substantia nigra relative to the contralateral hemisphere. These monkeys showed hypokinesia of the left forelimbs and hindlimbs. During mastication, MPTP-treated monkeys chewed preferentially on the left side, while untreated monkeys (n = 3) showed no preference for chewing side. The amplitude of vertical opening and closing movements was reduced in MPTP-treated monkeys, with a slight but significant increase in the lateral component of mandibular movements. The velocity of all phases of horizontal mandibular movements was reduced. In consequence, duration of the occlusal phase was increased, while duration of the closing phase was decreased in MPTP-treated monkeys. These findings indicate that during masticatory movements MPTP-treated monkeys chew preferentially on the side contralateral to loss of dopamine neurons, with reduced amplitude and velocity of mandibular movements. High-speed digital movement analysis is able to define and quantify abnormalities of orofacial movement topography as a sign of parkinsonism.
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http://dx.doi.org/10.1007/s00702-012-0768-0DOI Listing
August 2012

Kinetics of GABAB autoreceptor-mediated suppression of GABA release in rat insular cortex.

J Neurophysiol 2012 Mar 21;107(5):1431-42. Epub 2011 Dec 21.

Dept. of Pharmacology, Nihon Univ. School of Dentistry, Tokyo, Japan.

Release of GABA is controlled by presynaptic GABA receptor type B (GABA(B)) autoreceptors at GABAergic terminals. However, there is no direct evidence that GABA(B) autoreceptors are activated by GABA release from their own terminals, and precise profiles of GABA(B) autoreceptor-mediated suppression of GABA release remain unknown. To explore these issues, we performed multiple whole-cell, patch-clamp recordings from layer V rat insular cortex. Both unitary inhibitory and excitatory postsynaptic currents (uIPSCs and uEPSCs, respectively) were recorded by applying a five-train depolarizing pulse injection at 20 Hz. In connections from both fast-spiking (FS) and non-FS interneurons to pyramidal cells, the GABA(B) receptor antagonist CGP 52432 had little effect on the initial uIPSC amplitude. However, uIPSCs, responding to later pulses, were effectively facilitated. This CGP 52432-induced facilitation was prominent in the fourth uIPSCs, which were evoked 150 ms after the first uIPSC. The facilitation of uIPSCs was accompanied by an increase in the paired-pulse ratio. In addition, analysis of the coefficient of variation suggests the involvement of presynaptic mechanisms in CGP 52432-induced uIPSC facilitation. Paired-pulse stimulation (interstimulus interval = 150 ms) of presynaptic FS cells revealed that the second uIPSC was also facilitated by CGP 52432, which had little effect on the amplitude and interevent interval of miniature IPSCs. In contrast, uEPSCs, responding to all five stimulations of a presynaptic pyramidal cell, were less affected by CGP 52432. These results suggest that a single presynaptic action potential is sufficient to activate GABA(B) autoreceptors and to suppress GABA release in the cerebral cortex.
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http://dx.doi.org/10.1152/jn.00813.2011DOI Listing
March 2012

D(2)-like dopamine receptors differentially regulate unitary IPSCs depending on presynaptic GABAergic neuron subtypes in rat nucleus accumbens shell.

J Neurophysiol 2012 Jan 2;107(2):692-703. Epub 2011 Nov 2.

Department of Pharmacology, Nihon University School of Dentistry, Tokyo, Japan.

In the nucleus accumbens (NAc), a medium spiny (MS) neuron receives GABAergic inputs from two major sources: fast-spiking (FS) neurons and other, adjacent MS neurons. These two types of inhibitory synapses are considered to play different roles in output activities, i.e., FS→MS connections suppress output from the NAc whereas MS→MS connections contribute to lateral inhibition. In the present study, we focused on the electrophysiological properties of unitary inhibitory postsynaptic currents (uIPSCs) obtained from MS→MS connections and FS→MS connections and examined the effects of quinpirole, a dopamine D(2)-like receptor agonist, on uIPSCs with multiple whole cell patch-clamp recording. Application of quinpirole (1 μM) reliably suppressed the amplitude of uIPSCs by 29.6% in MS→MS connections, with increases in paired-pulse ratio and failure rate. The suppressive effects of quinpirole on uIPSCs were mimicked by 1 μM PD128907, a D(2/3) receptor agonist, whereas quinpirole-induced suppression of uISPCs was blocked by preapplication of 1 μM sulpiride or 10 μM nafadotride, both D(2/3) receptor antagonists. On the other hand, quinpirole (1 μM) had divergent effects on FS→MS connections, i.e., quinpirole increased uIPSC amplitude in 38.1% of FS→MS connections and 23.8% of FS→MS connections were suppressed by quinpirole. Analysis of coefficient of variation in uIPSC amplitude implied the involvement of presynaptic mechanisms in quinpirole-induced effects on uIPSCs. These results suggest that activation of D(2)-like receptors facilitates outputs from MS neurons in the NAc by reducing lateral inhibition during a dormant period of FS neuron activities.
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http://dx.doi.org/10.1152/jn.00281.2011DOI Listing
January 2012

In vivo neurochemical evidence that newly synthesised GABA activates GABA(B), but not GABA(A), receptors on dopaminergic nerve endings in the nucleus accumbens of freely moving rats.

Neuropharmacology 2012 Feb 28;62(2):907-13. Epub 2011 Sep 28.

Department of Pharmacology, Nihon University School of Dentistry, 1-8-13, Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.

GABA released from accumbal GABAergic interneurons plays an inhibitory role in the regulation of dopamine efflux through GABA(B) and GABA(A) receptors located on accumbal dopaminergic nerve endings. The cytosolic newly synthesised GABA alters vesicular GABA levels and, accordingly, the amount of GABA released from the neuron. Therefore, we hypothesised that glutamic acid decarboxylase (GAD) which generates GABA in accumbal GABAergic neurons, at least partly determines the GABA receptor subtype-mediated GABAergic tonus. To (in)validate this hypothesis, in vivo microdialysis was used to study the effects of an intra-accumbal infusion of the GAD inhibitor l-allylglycine (allylglycine) on the accumbal dopamine efflux of freely moving rats. The intra-accumbal infusion of allylglycine (50.0, 250.0 and 500.0 nmol) dose-dependently increased the accumbal dopamine levels. The co-administration of tetrodotoxin (720 pmol) suppressed the allylglycine (500.0 nmol)-induced dopamine efflux. The intra-accumbal infusion of GABA(B) receptor agonist baclofen (2.5 and 5.0 nmol) inhibited the allylglycine (500.0 nmol)-induced dopamine efflux. The baclofen's effects were counteracted by GABA(B) receptor antagonist saclofen (10.0 nmol). Neither GABA(A) receptor agonist (muscimol: 25.0 and 250.0 pmol) nor antagonist (bicuculline: 50.0 pmol) altered the allylglycine (250.0 and 500.0 nmol)-induced dopamine efflux. The present study provides in vivo neurochemical evidence that newly synthesised GABA that exerts an inhibitory tonus on the accumbal dopaminergic activity, acts at the level of GABA(B) receptors, but not GABA(A) receptors. The present study also shows that there is an allylglycine-insensitive GABA pool that release GABA exerting an inhibitory control of the accumbal dopaminergic activity, at the level of GABA(A) receptors. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
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http://dx.doi.org/10.1016/j.neuropharm.2011.09.021DOI Listing
February 2012

Spatiotemporal dynamics of long-term potentiation in rat insular cortex revealed by optical imaging.

Neurobiol Learn Mem 2011 Oct 9;96(3):468-78. Epub 2011 Aug 9.

Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.

Long-term potentiation (LTP) of the gustatory cortex (GC), a part of the insular cortex (IC) around the middle cerebral artery, is a key process of gustatory learning and memory, including conditioned taste aversion learning. The rostral (rGC) and caudal GC (cGC) process different tastes; the rGC responds to hedonic and the cGC responds to aversive tastes. However, plastic changes of spatial interaction of excitatory propagation between the rGC and cGC remain unknown. The present study aimed to elucidate spatiotemporal profiles of excitatory propagation, induced by electrical stimulation (five train pulses) of the rGC/cGC before and after LTP induction, using in vivo optical imaging with a voltage-sensitive dye. We demonstrated that tetanic stimulation of the cGC induced long-lasting expansion of the excitation responding to five train stimulation of the cGC, and an increase in amplitude of optical signals in the IC. Excitatory propagation after LTP induction spread preferentially toward the rostral IC: the length constant (λ) of excitation, obtained by fitting optical signals with a monoexponential curve, was increased to 121.9% in the rostral direction, whereas λ for the caudal, dorsal, and ventral directions were 48.9%, 44.2%, and 62.5%, respectively. LTP induction was prevented by pre-application of D-APV, an NMDA receptor antagonist, or atropine, a muscarinic receptor antagonist, to the cortical surface. In contrast, rGC stimulation induced only slight LTP without direction preference. Considering the different roles of the rGC and cGC in gustatory processing, these characteristic patterns of LTP in the GC may be involved in a mechanism underlying conversion of palatability.
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http://dx.doi.org/10.1016/j.nlm.2011.07.003DOI Listing
October 2011

Behavioral pharmacology of orofacial movement disorders.

Int Rev Neurobiol 2011 ;97:1-38

Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.

Dysfunction in orofacial movement is evident in patients with schizophrenia, Parkinson's disease and Huntington's disease. In animal studies on orofacial dyskinesia, these neurological disorders have been considered as a starting point to examine the pathophysiology and mechanisms underlying the symptoms. There is circumstantial evidence that orofacial dyskinesia in humans might be the consequence of hyperfunctioning mesolimbic-pallidal circuitry, in which the mesolimbic region occupies a central role, in contrast to typical Parkinson-like symptoms which involve hypofunction in the nigrostriato-nigral circuity. Studies in animals suffer from technical difficulties concerning the assessment of orofacial behaviors. There are some experimental designs that provide detailed information on the amplitude and the frequency of the jaw movements. By using such methods, the involvement of neurotransmitter systems and functional neural connections within the basal ganglia has been studied in rat rhythmical jaw movements. Regarding neurotransmitter systems, dopaminergic, cholinergic, γ-aminobutyric acid (GABA)ergic and glutamaterigic systems have been shown to be involved in rat rhythmical jaw movements. The involved neural connections have also been investigated, focusing on the differential role between the dorsal and ventral part of the striatum, the shell and core of the nucleus accumbens and the output pathways from the striatum and the nucleus accumbens. Taking available clinical and experimental evidence, the orofacial dyskinesias are thought to arise when hierarchically lower order output stations of the mesolimbic region start to dysfunction as a consequence of the arrival of distorted information sent by the mesolimbic region. This review seeks to provide an overview of prior and recent findings across several orofacial movement disorders and interpret new insights in the context of the limitations of behavioral pharmacology and prior knowledge of the regulation of behavior by dopamine receptors and other related neuronal systems.
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http://dx.doi.org/10.1016/B978-0-12-385198-7.00001-1DOI Listing
October 2011

Phenotypic disruption to orofacial movement topography in conditional mutants with generalized CamKIIa/Cre D1Tox versus striatal-specific DARPP-32/Cre D1Tox ablation of D1 dopamine receptor-expressing cells.

Synapse 2011 Sep 10;65(9):835-42. Epub 2011 Mar 10.

Advanced Research Institute for the Sciences and Humanities, Nihon University, Tokyo 102, Japan.

Orofacial movements were quantified in (a) DARPP-32/Cre D1Tox mutants, having progressive loss of D1 dopamine receptor expressing striatal medium spiny neurons and (b) CamKIIa/Cre D1Tox mutants, having progressive, generalized loss of forebrain D1 receptor expressing cells. Horizontal jaw movements and tongue protrusions were reduced in DARPP-32/Cre but not in CamKIIa/Cre mutants; head and vibrissae movements were increased in DARPP-32/Cre but decreased in CamKIIa/Cre mutants. In drug challenge studies, tongue protrusions were increased in CamKIIa/Cre mutants following vehicle, suggesting a stress-related phenotype. These findings indicate that mice with progressive loss of striatal-specific D1 receptor expressing cells have an orofacial phenotype that may be modulated by the loss of extrastriatal D1 receptor expressing cells. As progressive loss of D1 dopamine receptor-expressing cells is a hallmark feature of Huntington's disease (HD), these findings may inform the functional role of loss of this cell population in the overall pathobiology of HD.
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http://dx.doi.org/10.1002/syn.20910DOI Listing
September 2011

Morphine modulation of thrombospondin levels in astrocytes and its implications for neurite outgrowth and synapse formation.

J Biol Chem 2010 Dec 2;285(49):38415-27. Epub 2010 Oct 2.

E. A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University, St. Louis, Missouri 63104, USA.

Opioid receptor signaling via EGF receptor (EGFR) transactivation and ERK/MAPK phosphorylation initiates diverse cellular responses that are cell type-dependent. In astrocytes, multiple μ opioid receptor-mediated mechanisms of ERK activation exist that are temporally distinctive and feature different outcomes. Upon discovering that chronic opiate treatment of rats down-regulates thrombospondin 1 (TSP1) expression in the nucleus accumbens and cortex, we investigated the mechanism of action of this modulation in astrocytes. TSP1 is synthesized in astrocytes and is released into the extracellular matrix where it is known to play a role in synapse formation and neurite outgrowth. Acute morphine (hours) reduced TSP1 levels in astrocytes. Chronic (days) opioids repressed TSP1 gene expression and reduced its protein levels by μ opioid receptor and ERK-dependent mechanisms in astrocytes. Morphine also depleted TSP1 levels stimulated by TGFβ1 and abolished ERK activation induced by this factor. Chronic morphine treatment of astrocyte-neuron co-cultures reduced neurite outgrowth and synapse formation. Therefore, inhibitory actions of morphine were detected after both acute and chronic treatments. An acute mechanism of morphine signaling to ERK that entails depletion of TSP1 levels was suggested by inhibition of morphine activation of ERK by a function-blocking TSP1 antibody. This raises the novel possibility that acute morphine uses TSP1 as a source of EGF-like ligands to activate EGFR. Chronic morphine inhibition of TSP1 is reminiscent of the negative effect of μ opioids on EGFR-induced astrocyte proliferation via a phospho-ERK feedback inhibition mechanism. Both of these variations of classical EGFR transactivation may enable opiates to diminish neurite outgrowth and synapse formation.
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http://dx.doi.org/10.1074/jbc.M110.109827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992274PMC
December 2010

Purinergic receptors are involved in tooth-pulp evoked nocifensive behavior and brainstem neuronal activity.

Mol Pain 2010 Sep 22;6:59. Epub 2010 Sep 22.

Department of Physiology, Nihon University School of Dentistry, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai Chiyoda-ku, Tokyo, 101-8310, Japan.

Background: To evaluate whether P2X receptors are involved in responses to noxious pulp stimulation, the P2X3 and P2X2/3 receptor agonist α,β-methyleneATP (α,β-meATP) was applied to the molar tooth pulp and nocifensive behavior and extracellular-signal regulated kinase (ERK) phosphorylation in trigeminal spinal subnucleus caudalis (Vc), trigeminal spinal subnucleus interpolaris (Vi), upper cervical spinal cord (C1/C2) and paratrigeminal nucleus (Pa5) neurons were analyzed in rats.

Results: Genioglossus (GG) muscle activity was evoked by pulpal application of 100 mM α,β-meATP and was significantly larger than GG activity following vehicle (phosphate-buffered saline PBS) application (p < 0.01). The enhanced GG muscle activity following 100 mM α,β-meATP was significantly reduced (p < 0.05) by co-application of 1 mM TNP-ATP (P2X1, P2X3 and, P2X2/3 antagonist). A large number of pERK-LI cells were expressed in the Vc, Vi/Vc, C1/C2 and Pa5 at 5 min following pulpal application of 100 mM α,β-meATP compared to PBS application to the pulp (p < 0.05). The pERK-LI cell expression and GG muscle activity induced by 100 mM α,β-meATP pulpal application were significantly reduced after intrathecal injection of the MAPK/ERK kinase (MEK) inhibitor PD 98059 and by pulpal co-application of 1 mM TNP-ATP (p < 0.05).

Conclusions: The present findings suggest that activation of P2X3 and P2X2/3 receptors in the tooth pulp is sufficient to elicit nociceptive behavioral responses and trigeminal brainstem neuronal activity.
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http://dx.doi.org/10.1186/1744-8069-6-59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146069PMC
September 2010

Dopamine D₁-like receptors play only a minor role in the increase of striatal dopamine induced by striatally applied SKF38393.

Eur J Pharmacol 2010 Dec 9;648(1-3):80-6. Epub 2010 Sep 9.

Department of Anaesthesiology, Nihon University School of Dentistry, 1-8-13, Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.

We studied the effects of the intra-striatal infusion of Ca(2+)-free medium on the intra-striatal injection of 0.5 μg SKF38393-induced striatal dopamine efflux. It is discussed that the amount of extracellular, striatal dopamine seen after striatally applied SKF38393, is the overall result of the (a) release of dopamine from the alpha-methyl-para-tyrosine-sensitive and Ca(2+)-insensitive pool of newly synthesised dopamine, (b) release of dopamine from the reserpine-sensitive and Ca(2+)-sensitive storage pool, (c) inhibition of uptake of dopamine into nerve terminals and glial cells, and (d) facilitation respectively of the inhibition of uptake into blood vessels: dopamine D₁-like receptors play only a very limited role in these processes. The present study underlines our previous notion that the effects of SKF38393 cannot simply be ascribed to the dopamine D₁-like receptor stimulation (Saigusa et al., 2009): in fact, the present study clearly reveals that SKF38393 is not at all selective in that respect.
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http://dx.doi.org/10.1016/j.ejphar.2010.08.031DOI Listing
December 2010