bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for Functional Differences between Entopeduncular Nucleus and Substantia Nigra: Effects of APV (DL‐2‐amino‐5‐phosphonovaleric acid) Microinfusion on Reaction Time Performance in the Rat
Authors: Baunez Christelle , Amalric Marianne 
Published: April 2006

AbstractOveractivity of the excitatory amino acid outputs of the subthalamic nucleus (STN) has recently been found to be one of the cascade of subsequent disruptions caused by nigrostriatal dopaminergic degeneration in Parkinson's disease. The respective contribution of the excitatory glutamatergic output structures of the STN [i.e. the globus pallidus (GP), entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr)] to the control of movement is not known, however. To investigate further the function of glutamatergic transmission through NMDA receptor subtypes in these three structures, the effects of discrete local infusion of a competitive receptor antagonist, DL‐2‐amino‐5‐phosphonovaleric acid (APV), into the EP, GP and SNr were tested in rats performing a reaction time task. Bilateral infusion of APV into the different output structures of the STN differentially impaired the performance of rats trained to release a lever after the onset of a visual stimulus within a time limit to obtain a food reward. Infusion of APV (0.25 and 0.5 μg/0.5 μl) into the SNr was found to induce behavioural deficits characterized by a dramatic increase in the number of premature lever releases and decreased mean reaction time. In contrast, the infusion of APV at a dose of 0.25 μg into the GP or EP was found to induce a motor initiation deficit characterized by an increased number of delayed responses (lever release after the time limit) and increased mean reaction time. At a dose of 0.5 μg, a premature responding deficit was added to the previous motor impairment. Interestingly, when APV was infused simultaneously into the GP and SNr in the same animals, the behavioural effects tended to be similar to those observed after a single infusion into the SNr. Altogether, these results reveal that the different functional weight of the three main output pathways originating at the STN level is t.o. The behavioural deficits induced by NMDA receptor blockade in the SNr were similar to those observed previously after a neurotoxic lesion of the STN, suggesting that NMDA receptors in this structure play a major role as a functional output of the STN. Furthermore, regarding the differential effects produced by the same dose of APV in the SNr and the EP, these two structures, which are classically believed to be functionally linked should not be considered as the same functional entity in the organization of basal ganglia outflow.
Thiocyanate Ions Inhibit AMPA‐activated Currents in Recombinant non‐NMDA Receptors Expressed in Xenopus laevis Oocytes: the Role of the GluR2 Subunit
Authors: Eugène D. , Moss S. J. , Smart T. G. 
Published: April 2006

AbstractThe functional interaction of thiocyanate (SCN‐) ions with recombinant non‐N‐methyl‐D‐aspartate receptors was examined by studying α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)‐ and kainic acid (KA)‐activated currents in Xenopus laevis oocytes. Recombinant receptors were expressed after microinjection of oocytes with combinations of cDNAs or cRNAs encoding for GluR1, GluR2, GluR2(R586Q), GluR3 or GluR6 subunits. When the GluR2 subunit was expressed with GluR1, SCN‐ (2 mM) inhibited the responses to 50 μM AMPA, whereas responses to 100 μM KA were slightly increased and responses to 200 μM L‐glutamate were unaffected. Equilibrium concentration‐response curves for AMPA were antagonized in a non‐competitive manner by SCN‐ with a reduction in the EC50. The inhibitory effects of SCN‐ were unaffected by prior reduction of receptor desensitization with either 10 μM Concanavalin‐A or 0.5 mM diazoxide. AMPA‐activated currents recorded from homomeric GluR1 or GluR3 receptors were not affected by SCN‐, and GluR6 homomeric receptors, which are sensitive to KA but not to AMPA, were also unaffected. In contrast, AMPA activation of homomeric GluR2(R586Q) subunit receptors, or combinations of GluR1 or GluR3 + GluR2(R586Q) subunits, were markedly inhibited by SCN‐. In addition, the inhibitory effect of AMPA on KA‐activated responses on these heteromeric receptors, was enhanced by SCN‐. These results indicate that SCN‐ exert an inhibitory effect on ‘AMPA receptors’but only when the recombinant non‐NMDA receptor is a GluR2 homomer, or when GluR2 subunits are present as part of a heteromeric combination. Moreover, this inhibitory effect was unaffected by the ‘Q/R’site in the presumed second transmembrane domain, since currents mediated by the GluR2(R586Q) subunit were also susceptible to inhibition by SCN‐. Thus the inhibition was not related to the rectification properties or calcium permeability of the non‐NMDA receptors. It is suggested that the GluR2 subunit may have a specific binding site for anions which could modulate the function of non‐NMDA receptors and that SCN‐ may be a useful probe for the detection of these subunits in native neurons.
Maturation‐dependent Modulation of Apoptosis in Cultured Cerebellar Granule Neurons by Cytokines and Neurotrophins
Authors: de Luca Ariane , Weller Michael , Frei Karl , Fontana Adriano 
Published: April 2006

AbstractImmature cerebellar granule neurons die by apoptosis within 1 week in vitro unless maintained in depolarizing (high) concentrations of potassium (25 mM K+). Neurons allowed to survive and differentiate in high K+ medium for several days in vitro are still induced to undergo apoptosis when switched back to physiological (low) concentrations of K+ (5 mM). Here we have investigated the effects of various cytokines and growth factors in these two well‐defined paradigms of neuronal apoptosis. Tumour necrosis factor‐α, leukaemia inhibitory factor, ciliary neurotrophic factor, interleukin‐10 and interleukin‐13 delayed apoptosis and prolonged survival of cerebellar granule neurons maintained in low K+ medium. The effect observed required continuous exposure of the cultures to the cytokines and appeared not to involve modulation of Bcl‐2 protein expression. Brain‐derived neurotrophic factor accelerated neuronal death in low K+ medium. In contrast, when apoptosis of the neurons was precipitated by switching mature high K+ neurons to low K+ medium, neither tumour necrosis factor‐α, leukaemia inhibitory factor, ciliary neurotrophic factor, interleukin‐10 nor interleukin‐13 prevented apoptosis. When testing the cytokines and growth factors for their capacity to alter N‐methyl‐D‐aspartate receptor‐mediated excitotoxicity of differentiated cerebellar granule neurons, no significant effect was observed. These data appear to define a maturation‐dependent modulation of cerebellar granule cell survival by cytokines and neurotrophic factors that are expressed in a developmental pattern in the mammalian brain.
Long‐term Treatment with some Methylxanthines Decreases the Susceptibility to Bicuculline‐ and Pentylenetetrazol‐induced Seizures in Mice. Relationship to c‐ios Expression and Receptor Binding
Authors: Johansson Björn , Georgiev Vasil , Kuosmanen Tarja , Fredholm Bertil B. 
Published: April 2006

AbstractThe effects of long‐term oral administration of low doses of caffeine (0.3 g/l) and its metabolites theophylline, theobromine and paraxanthine (each at 0.5 g/l in drinking water) on bicuculline‐ and pentylenetetrazol (PTZ) ‐induced seizures and c‐fos expression were studied in mice. In addition, adenosine and benzodiazepine receptor density was examined. The plasma levels of the methylxanthines were much higher during the active period at night than during the day. The maximal level of caffeine was 14 μM. Brain theophylline levels (8‐13 nmol/g) tended to be higher and more constant than brain caffeine levels in caffeine‐consuming mice. Clonic seizures induced by bicuculline (4 mg/kg i.p.) were significantly reduced in severity by 14 day caffeine treatment and mortality was also reduced. Long‐term treatment with caffeine metabolites was less effective. The seizures induced by PTZ (60 mg/kg i.p.) were also significantly reduced by long‐term caffeine treatment. After bicuculline or PTZ treatment, c‐fos mRNA expression was weaker in the cerebral cortex in animals receiving caffeine, irrespective of whether the animals had seizures or not. No significant changes in the binding of adenosine receptor ligands or benzodiazepines were seen after long‐term caffeine treatment. These results show that long‐term treatment with caffeine in a dose that is commonly seen in humans decreases the seizures induced by bicuculline, and to a lesser extent, those induced by PTZ. This may be related to a decreased neuronal excitability. The effect is due to the combined effects of theophylline, to which caffeine is metabolized in brain, and of caffeine itself, but could not be ascribed to changes in A1 and A2A adenosine or benzodiazepine receptors.
GABA and Glycine in Synaptic Glomeruli of the Rat Spinal Dorsal Horn
Authors: Todd A. J. 
Published: April 2006

AbstractThe superficial dorsal horn of rat spinal cord contains two types of synaptic glomerulus, which are centred around the terminals of unmyelinated and myelinated primary afferents respectively. Both types of glomerulus contain GABAergic axons and dendrites, which are thought to originate from local inhibitory interneurons. Some of the dendrites contain synaptic vesicles, and may be presynaptic to the central axon at dendroaxonic synapses. In order to determine whether GABAergic structures in the two types of glomerulus are derived from different populations of interneurons, a quantitative post‐embedding immunogold study of GABA‐ and glycine‐immunoreactivity in rat dorsal horn was performed. In type I glomeruli, all of the peripheral axons and most vesicle‐containing dendrites were GABA‐immunoreactive, but only one of 32 axons and none of the vesicle‐containing dendrites was glycine‐immunoreactive. In contrast, most of the peripheral axons and some of the vesicle‐containing dendrites in type II glomeruli possessed both GABA‐ and glycine‐immunoreactivity. This strongly suggests that different types of inhibitory interneuron in the dorsal horn are associated with the two types of glomerulus. It is therefore likely that different populations of interneurons mediate presynaptic inhibition of unmyelinated and myelinated primary afferents.
DA Uptake Sites, D1, and D2 Receptors, D2 and Preproenkephalin mRNAs and Fos Immunoreactivity in Rat Striatal Subregions after Partial Dopaminergic Degeneration
Authors: Chritin M. , Blanchard V. , Raisman‐Vozari R. , Feuerstein C. , Agid Y. , Javoy‐Agid F. , Savasta M. 
Published: April 2006

AbstractStereotaxic injection of a limited amount of 6‐ hydroxydopamine in the lateral part of the rat substantia nigra induces a partial degeneration of the nigrostriatal dopaminergic system. This animal model in which the destruction of the dopaminergic nigral cell population reaches ‐50% could be considered as a preclinical Parkinson's model. Autoradiography of dopaminergic uptake sites performed with a specific marker ([3H]GBR 12935) allowed the precise determination of dopaminergic denervated and non‐denervated areas in the striatum 1 month after partial lesion of the substantia nigra pars compacta. In both striatal areas, dopaminergic D1 and D2receptor densities and dopaminergic D2 and preproenkephalin mRNAs levels were measured by autoradiography and in situ hybridization coupled to an image analysis system. Our results show that in the denervated striatal subregion, none of the dopaminergic targets were modified, contrary to the observations made after complete lesion of the nigrostriatal DA system at the same post‐lesion delay. However, striatal Fos activation induced by amphetamine (5 mg/kg i.p., 2 h before killing) revealed that the number of Fos‐positive cells detected in the denervated striatal subregion was lower than that observed in the non‐denervated one. These data argue in favour of the existence of compensatory mechanisms different from the up‐regulation of DA receptor densities, thereby allowing the maintenance of striatal dopaminergic transmission. Such mechanisms could contribute to the delay of the appearance of neurological symptoms (which are reported to be clinically apparent only when depletion of striatal dopamine levels reaches near 80%) in Parkinsonian patients.
Differential Distribution of Syntaxin Isoforms 1A and 1B in the Rat Central Nervous System
Authors: Ruiz‐Montasell B. , Aguado F. , Majó G. , Chapman E. R. , Canals J. M. , Marsal J. , Blasi J. 
Published: April 2006

AbstractSyntaxin 1 binds to several proteins of the synaptic terminal and is a central component in the pathway of protein–protein interactions that underlies docking and fusion of synaptic vesicles. Molecular studies revealed the occurrence of two isoforms, syntaxin 1A and syntaxin 1B, which coexpress in neural tissues. However, they display differential expression patterns in endocrine cell types. We generated isoform‐specific antibodies that were used in Western blotting and immunocytochemical studies. First, we confirmed the sole presence of syntaxin 1A in endocrine pituitary cells. Second, we found distinctive immunolabelling patterns of each isoform in the rat olfactory system, hippocampus, striatum, thalamus and spinal cord. In addition, the principal white matter commissures displayed distinct immunoreactivity for each isoform. This report shows, for the first time, major differences between the distributions of syntaxin 1A and syntaxin 1B isoforms in the rat central nervous system.
Identification of a Determinant of Acetylcholine Receptor Gating Kinetics in the Extracellular Portion of the γ Subunit
Authors: Fucile Sergio , Mileo Anna M. , Grassi Francesca , Salvatore Anna M. , Alemà Stefano , Eusebi Fabrizio 
Published: April 2006

AbstractA large body of structure‐function studies has identified many of the functional motifs underlying ion permeation through acetylcholine receptor (AChR) channels. The structural basis of channel gating kinetics is, however, incompletely understood. We have previously identified a novel shorter form of the AChR γ subunit, which lacks the 52 amino acids within the extracellular amino‐terminal half, encoded by exon 5. To define the contribution of the missing domain to AChR channel function, we have transiently coexpressed the mouse short γ subunit (γs) with α, β and δ subunits in human cells and recorded single‐channel currents from the resulting AChRs. Our findings show that replacement of the γ by the γs subunit confers a long duration characteristic to AChR channel openings without altering unitary conductance sizes or receptor affinity for the transmitter. We also show that βγδSδ AChR channels exhibit a peculiar voltage sensitivity characterized by a short opening duration when the membrane potential is hyperpolarized. Together, these findings indicate that the domain in the extracellular amino‐terminal half of the γ subunit that encompasses a conserved disulphide loop and a critical tyrosine residue implicated in receptor oligomerization and insertion at the cell surface is a functional motif that also modulates AChR channel gating kinetics. The results also provide a molecular explanation of the functional diversity exhibited by skeletal muscle AChRs during development.
Neuronal Control of MHC Class II Inducibility in Rat Astrocytes and Microglia
Authors: Neumann H. , Boucraut J. , Hahnel C. , Misgeld T. , Wekerle H. 
Published: April 2006

AbstractWe analysed the inducibility of major histocompatibility complex (MHC) class II molecules of astrocytes and microglia in organotypic hippocampus slice cultures of Lewis rats. Treatment with interferon‐γ (IFN‐γ) resulted in the induction of MHC class II molecules on microglia preferentially in the injured marginal zones of the slice culture, but only sporadically in areas containing intact neuronal architecture. In astrocytes, inducibility of MHC class II molecules was even more strictly controlled. IFN‐γ treatment induced MHC class II expression only in the slice culture zones containing degenerated neurons, and not in the presence of functional neurons. After suppression of spontaneous neuronal activity of the slice culture by the sodium channel blocker tetrodotoxin, MHC class II molecules on astrocytes could be induced by IFN‐γ in areas with intact neuronal architecture, and microglia cells exhibited a higher level of expression. These data suggest that loss of neurons could result in MHC class II inducibility of glial cells, and thus in increased immune reactivity of nervous tissue.
Phenylglycines can Evoke Quisqualate‐primed Depolarizations in Rat Cingulate Cortex: An Effect Associated with [3H]DL‐AP4 Uptake
Authors: Sheardown Malcolm J. , Thomsen Christian 
Published: April 2006

AbstractDepolarization could be evoked in slices of rat cingulate cortex by the normally non‐excitatory compound L‐2‐amino‐4‐phosphonobutyrate (l‐AP4) if the slices had been sensitized by exposure to quisqualate. The magnitude of the response to l‐AP4 was dependent on the concentrations of both l‐AP4 and quisqualate and was inhibited by α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate receptor antagonism. A series of phenylglycine analogues were capable of evoking similar dose‐dependent depolarizations in the rat cingulate cortex following quisqualate sensitization, the most potent being (S)‐4‐carboxy‐3‐hydroxyphenylglycine. If the superfusate collected during application of (S)‐4‐carboxy‐3‐hydroxyphenylglycine to a quisqualate‐sensitized slice was administered to a slice not previously exposed to quisqualate, a small depolarization was obtained. All the compounds shown to be capable of evoking the quisqualate‐sensitized response showed affinity for the l‐AP4 uptake site whilst having no affinity at ionotropic glutamate receptors and different profiles of activity at metabotropic glutamate receptors. None of the compounds was active at the metabotropic glutamate 4a receptor. There was a statistically significant correlation between a compound's effectiveness in inhibiting [3H]DL‐AP4 uptake into rat cortical synaptosomes and its potency in evoking quisqualate‐sensitized depolarization. It is concluded that this response may be the result of hetero‐exchange between L‐AP4 ligands and quisqualate.
NMDA and Kainate‐evoked Release of Nitric Oxide and Classical Transmitters in the Rat Striatum: In Vivo Evidence that Nitric Oxide May Play a Neuroprotective Role
Authors: Kendrick Keith M. , Guevara‐Guzman Rosalinda , de la Riva Carlos , Christensen Jakob , Østergaard K. , Emson Piers C. 
Published: April 2006

AbstractThe effects of N‐methy‐d‐aspartate (NMDA), kainate, S‐α‐amino‐3‐hydroxyd‐5‐methyl‐4‐isoxazole propionate (AMPA) and KCI on striatal nitric oxide (NO), acetylcholine (ACh), dopamine (DA), serotonin (5‐HT), aspartate (ASP), glutamate (GLU) and γ‐aminobutyric acid (GABA) release were measured in anaesthetized rats in vivo by microdialysis and in vitro in organotypic slice cultures. Local NMDA (1–100 μM) infusion by retrodialysis dose‐dependently increased levels of classical transmitters, NO2‐, NO3‐, ctrulline and arginine at similar thresholds (10 γM) Similar patterns of NMDA‐evoked (50 μM) release were seen in striatal cultures. NMDA‐evoked changes were all calcium‐dependent and blocked by NMDA (APV or MK‐801) but not AMPN/kainate (DNQX) receptor antagonists, excepting DA which could be prevented by both. In vivo, kainate increased NO2‐, NO3‐, CIT and ARG levels at 50 and 100 μM but was less potent than NMDA. Kainate also evoked significant Ach1 DA and GLU release dose‐dependently starting at 1–10 μM whereas 5‐HT, ASP and GABA required 50 or 100 μM doses. Kainate effects were inhibited by DNQX, but not by APV, and were calcium‐dependent. AMPA failed to alter NO2‐, NO3‐, CIT or ARG levels at 50 or 100 μM doses but dose‐dependently increased ACh and DA. Similar results were seen with kainate (50 μM) and AMPA (50 μM) in vitro KCI evoked NO2‐, NO3‐, CIT and ARG release as well as that of the classical transmitters in vivo and in vitro. In vivo administration of the NO synthase inhibitor L‐nitroarginine (L‐NARG; 100 μM) significantly reduced NO2‐, NO3‐ and CIT levels and prevented NMDA, kainate or KCI‐evoked increases. It also potentiated ACh, ASP, GLU and GABA release and reduced that of DA in response to 50 μM NMDA whereas treatment with an NO‐donor (SNAP; 10 μM) significantly reduced evoked ACh, ASP and GLU release. The NO synthase inhibitor L‐NARG potentiated kainate‐evoked ACh release and reduced that of DA, although less potently than NMDA, but it had no effect on KCI‐evoked transmitter release. Overall, these results show that both NMDA and kainate increase striatal NO release at similar dose‐thresholds as for classical transmitter release suggesting that NO is dynamically released under physiological and not just pathological conditions. Reduction of striatal NO levels also potentiates calcium‐dependent transmitter release in response to NMDA and, to a lesser extent, kainate, whereas increasing them reduces it. This is consistent with a role for NO as a neuroprotective agent in this region acting to desensitize NMDA receptors.
Protein Kinases in the Rat Nucleus Accumbens are Involved in the Aversive Component of Opiate Withdrawal
Authors: Valverde Olga , Tzavara Eleni , Hanoune Jacques , Roques Bernard P. , Maldonado Rafael 
Published: April 2006

AbstractThe specific participation of protein kinases in the expression of the somatic signs of morphine withdrawal has been previously demonstrated, suggesting that changes in intracellular signalling systems are involved in opioid addiction. In the present study, the involvement of protein kinases in the aversive/dysphoric effects of morphine abstinence has been investigated in the nucleus accumbens, because of the critical role played by the mesolimbic system in the rewarding effects of opioids. Rats were chronically treated with morphine, twice a day for 5 days, with doses progressively increased from 5 to 30 mg/kg (i‐p.). In addition, microinjections into the nucleus accumbens of the serine‐threonine kinase inhibitors H7 or H8 (1 or 10 nmol per side) or saline once daily were also given, both in control and in morphine‐treated animals. After these chronic treatments, withdrawal syndrome was induced by naloxone administration (0.1 mg/kg, s. c.), and the motivational component of morphine abstinence was studied using the place aversion paradigm. When administered at the highest dose (10 nmol), H7 and H8 strongly reduced the place aversion induced by naloxone in morphine dependent animals. Protein kinase inhibitors did not induce significant behavioural responses in non‐dependent animals. Chronic morphine treatment induced a selective up‐regulation of adenylate cyclase activity in the amygdala, without affecting other brain regions. The morphine‐increased adenylate cyclase activity in amygdala was reversed by the chronic intra‐accumbens microinjection of H7 or H8. These results suggest that serine‐threonine kinases in the nucleus accumbens play an important role in the emotional/dysphoric properties which characterize opiate withdrawal.