bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is dopamine the answer? Other systems in the neurochemical effects of psychostimulants
Authors: Izenwasser S. 
Published: July 2010

For over 20 years, the focus of studies examining the neurochemical and behavioral effects of cocaine and other psychostimulants has been on dopamine. Many behavioral studies have shown that dopamine plays an important role in the reinforcing and behavioral effects of cocaine. Cocaine binds to the dopamine transporter and inhibits dopamine uptake. While there are some effects of cocaine on dopamine receptors, dopamine levels, and the dopamine transporter, these neurochemical studies have not been able to account fully for the altered behavioral effects of cocaine following chronic cocaine administration. Recent studies by Kantak et al. have shown that the reinforcing effects of psychostimulants depend upon activation of brain nitric oxide synthase. In addition, Rocha et al. have reported that cocaine is self‐administered in animals lack dopamine transporters. This finding suggests that other neurochemical components are necessary for the reinforcing effects (and hence the abuse) of cocaine. Since cocaine binds to dopamine, norepinephrine and serotonin transporters, it is likely that a combination of effects on these systems may be responsible for the behavioral effects of cocaine. Mu‐ and kappa‐opioids regulate dopamine and serotonin and this regulation plays a role in the effects of cocaine (Izenwasser et al.). Unterwald and colleagues have shown that there are large effects of cocaine on opioid receptors and second messenger regulation. These studies show that there are interactions between multiple systems and that these interactions are important factors in the effects of abused drugs, perhaps more important than activation of dopaminergic systems alone. These findings will be discussed in terms of the implications for the development of treatments for cocaine abuse.
Iron porphyrin treatment extends survival in a transgenic animal model of amyotrophic lateral sclerosis
Authors: Wu Annie S. , Kiaei Mahmoud , Aguirre Norberto , Crow John P. , Calingasan Noel Y. , Browne Susan E. , Beal M. Flint 
Published: July 2010

AbstractOxidative damage, produced by mutant Cu/Zn superoxide dismutase (SOD1), may play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating motor neuron degenerative disease. A novel approach to antioxidant therapy is the use of metalloporphyrins that catalytically scavenge a wide range of reactive oxygen and reactive nitrogen species. In this study, we examined the therapeutic potential of iron porphyrin (FeTCPP) in the G93A mutant SOD1 transgenic mouse model of ALS. We found that intraperitoneal injection of FeTCPP significantly improved motor function and extended survival in G93A mice. Similar results were seen with a second group of mice wherein treatment with FeTCPP was initiated at the onset of hindlimb weakness—roughly equivalent to the time at which treatment would begin in human patients. FeTCPP‐treated mice also showed a significant reduction in levels of malondialdehyde (a marker of lipid peroxidation), in total content of protein carbonyls (a marker of protein oxidation), and increased neuronal survival in the spinal cord. These results therefore provide further evidence of oxidative damage in a mouse model of ALS, and suggest that FeTCPP could be beneficial for the treatment of ALS patients.
Ethanol specifically decreases peroxisome proliferator activated receptor β in B12 oligodendrocyte‐like cells
Authors: Leisewitz Andrea V. , Jung Juan E. , Perez‐Alzola Patricia , Fuenzalida Karen M. , Roth Alejandro , Inestrosa Nibaldo C. , Bronfman Miguel 
Published: July 2010

AbstractPeroxisome proliferator activated receptors (PPARs) are nuclear receptors that control important genes involved in lipid metabolism. Their role in nerve cells is uncertain, although anomalous myelination of the corpus callosum has been described in the PPARβ‐null mouse, and abnormalities of this tissue have been documented in fetal alcohol syndrome in humans. We report here that ethanol treatment of B12 oligodendrocyte‐like cells induces a concentration‐ and time‐dependent decrease in the mRNA and protein levels of PPARβ, with no effect on PPARα or PPARγ. The effect on PPARβ is seen as an increase in mRNA degradation, as assessed by run‐off assays, due to a significant decrease in PPARβ mRNA half‐life, with no observed changes in intracellular localization. Our results suggest a possible link between PPARβ function and ethanol‐induced abnormal myelination in oligodendrocytes.
Amphetamine‐induced c‐fosmRNA expression in the caudate‐putamen and subthalamic nucleus: interactions between dose, environment, and neuronal phenotype
Authors: Uslaner Jason M. , Norton Camille S. , Watson Stanley J. , Akil Huda , Robinson Terry E. 
Published: July 2010

AbstractWhen administered in a novel environment relatively low doses of amphetamine induce c‐fosmRNA in the subthalamic nucleus (STN) and in preproenkephalin mRNA‐containing (ENK+) neurons in the caudate‐putamen (CPu). When administered at home, however, low doses of amphetamine do not produce these effects. Environmental novelty also facilitates the behavioral effects of acute and repeated amphetamine, but this is dose‐dependent. The purpose of the present experiment therefore was to determine if the effect of context on amphetamine‐induced c‐fosexpression is also dose‐dependent. It was found that: (i) No dose of amphetamine tested (1–10 mg/kg) induced c‐fosin many ENK+ cells when given at home. (ii) When given in a novel environment low to moderate doses of amphetamine (1–5 mg/kg) induced c‐fosin substantial numbers of ENK+ cells, but the highest dose examined (10 mg/kg) did not. (iii) Environmental novelty enhanced the ability of low to moderate doses of amphetamine to induce c‐fosin the STN, but the highest dose of amphetamine induced robust c‐fosmRNA expression in the STN regardless of context. The results do not support the idea that engaging ENK+ cells, at least as indicated by c‐fosmRNA expression, is critical to produce robust behavioral sensitization, but do suggest a possible role for the STN. Furthermore, the results highlight the importance of drug–environment interactions on the neurobiological effects of drugs, and have implications for thinking about the circuits by which context modulates the acute and long‐lasting consequences of amphetamine treatment.
The roles of calcium/calmodulin‐dependent and Ras/mitogen‐activated protein kinases in the development of psychostimulant‐induced behavioral sensitization
Authors: Licata Stephanie C. , Pierce R. Christopher 
Published: July 2010

AbstractAlthough the development of behavioral sensitization to psychostimulants such as cocaine and amphetamine is confined mainly to one nucleus in the brain, the ventral tegmental area (VTA), this process is nonetheless complex, involving a complicated interplay between neurotransmitters, neuropeptides and trophic factors. In the present review we present the hypothesis that calcium‐stimulated second messengers, including the calcium/calmodulin‐dependent protein kinases and the Ras/mitogen‐activated protein kinases, represent the major biochemical pathways whereby converging extracellular signals are integrated and amplified, resulting in the biochemical and molecular changes in dopaminergic neurons in the VTA that represent the critical neuronal correlates of the development of behavioral sensitization to psychostimulants. Moreover, given the important role of calcium‐stimulated second messengers in the expression of behavioral sensitization, these signal transduction systems may represent the biochemical substrate through which the transient neurochemical changes associated with the development of behavioral sensitization are translated into the persistent neurochemical, biochemical and molecular alterations in neuronal function that underlie the long‐term expression of psychostimulant‐induced behavioral sensitization.
Oligodendrocyte injury in multiple sclerosis: a role for p53
Authors: Wosik Karolina , Antel Jack , Kuhlmann Tanja , Brück Wolfgang , Massie Bernard , Nalbantoglu Josephine 
Published: July 2010

AbstractMultiple sclerosis (MS) is a neurological disorder characterized by myelin destruction and a variable degree of oligodendrocyte death. We have previously shown that overexpression of the transcription factor p53 can induce oligodendrocyte apoptosis. We investigated the mechanism of p53‐induced apoptosis using primary cultures of central nervous system‐derived adult human oligodendrocytes. Adenovirus‐mediated p53 overexpression resulted in up‐regulation of the death receptors Fas, DR4 and DR5 with subsequent caspase‐mediated apoptosis of the oligodendrocytes. The oligodendrocytes were protected from p53‐induced cell death by blocking signaling through Fas and/or tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) receptors. Although lower levels of p53 did not induce apoptosis, the increase in death receptor expression was sufficient to render the oligodendrocytes susceptible to apoptosis in the presence of exogenous Fas ligand and TRAIL. These ligands are present in the inflammatory milieu of active MS lesions. In situ analysis of active MS lesions revealed increased p53 expression in oligodendrocytes in lesions that featured oligodendrocyte apoptosis and cell loss. Our data provide evidence for a novel role for p53 in the pathogenesis of MS.
Secretoneurin promotes pertussis toxin‐sensitive neurite outgrowth in cerebellar granule cells
Authors: Gasser M. C. , Berti I. , Hauser K. F. , Fischer‐Colbrie R. , Saria A. 
Published: July 2010

AbstractThe neuropeptide secretoneurin (SN) is an endoproteolytic product of the chromogranin secretogranin II. We investigated the effects of SN on the differentiation of immature cerebellar granule cells derived from the external granular layer (EGL). Secretoneurin caused concentration‐dependent increases in neurite outgrowth, reflecting differentiation. The maximum effect was reached at a concentration of 100 nm SN. Secretoneurin immunoneutralization using specific antiserum significantly decreased neurite outgrowth; however, neurite morphology was altered. An affinity chromatography‐purified antibody significantly inhibited the outgrowth response to SN (p < 0.001) without altering the morphology. Binding studies suggest the existence of specific G‐protein‐coupled receptors on the surface of monocytes that recognize SN. Assuming that SN promotes neurite outgrowth in EGL cells by acting through a similar G‐protein‐coupled mechanism, we treated SN‐stimulated EGL cultures with pertussis toxin. Exposure to pertussis toxin (0.1 µg/mL) showed a significant inhibition of the SN‐induced outgrowth. To establish a second messenger pathway we used the protein kinase C inhibitor staurosporine. We found that EGL cell viability was not enhanced following chronic SN treatment for 24 h. These data indicate that SN is a novel trophic substance that can affect cerebellar maturation, primarily by accelerating granule cell differentiation through a signalling mechanism that is coupled to pertussis toxin‐sensitive G‐proteins.
Fluorescence resonance energy transfer to probe human M1 muscarinic receptor structure and drug binding properties
Authors: Ilien Brigitte , Franchet Christelle , Bernard Philippe , Morisset Séverine , Odile Weill Claire , Bourguignon Jean‐Jacques , Hibert Marcel , Galzi Jean‐Luc 
Published: July 2010

AbstractHuman M1 muscarinic receptor chimeras were designed (i) to allow detection of their interaction with the fluorescent antagonist pirenzepine labelled with Bodipy [558/568], through fluorescence resonance energy transfer, (ii) to investigate the structure of the N‐terminal extracellular moiety of the receptor and (iii) to set up a fluorescence‐based assay to identify new muscarinic ligands. Enhanced green (or yellow) fluorescent protein (EGFP or EYFP) was fused, through a linker, to a receptor N‐terminus of variable length so that the GFP barrel was separated from the receptor first transmembrane domain by six to 33 amino‐acids. Five fluorescent constructs exhibit high expression levels as well as pharmacological and functional properties superimposable on those of the native receptor. Bodipy‐pirenzepine binds to the chimeras with similar kinetics and affinities, indicating a similar mode of interaction of the ligand with all of them. From the variation in energy transfer efficiencies determined for four different receptor‐ligand complexes, relative donor (EGFP)‐acceptor (Bodipy) distances were estimated. They suggest a compact architecture for the muscarinic M1 receptor amino‐terminal domain which may fold in a manner similar to that of rhodopsin. Finally, this fluorescence‐based assay, prone to miniaturization, allows reliable detection of unlabelled competitors.
Regulation of neuritogenesis and synaptic transmission by msec7‐1, a guanine nucleotide exchange factor, in cultured Aplysia neurons
Authors: Huh Minjung , Han Jin‐Hee , Lim Chae‐Seok , Lee Seung‐Hee , Kim Seho , Kim Eunjoon , Kaang Bong‐Kiun 
Published: July 2010

Abstractmsec7‐1, a mammalian homologue of yeast sec7p, is known as a GDP/GTP exchange factor (GEF) for the ADP ribosylation factor (ARF) family of small GTPases. Here, we report that msec7‐1 overexpression in cultured Aplysia neurons leads to an extensive neuritogenesis in a GEF activity‐dependent manner through the modulation of the actin cytoskeleton. Similarly, the overexpression of ARNO, another mammalin GEF, produces extensive neuritogenesis in Aplysia neurons. In addition, msec7‐1 overexpression increases the number of varicosities with an altered size and shape in a GEF activity‐dependent manner. The overexpression of msec7‐1 in pre‐synaptic sensory neurons co‐cultured with post‐synaptic target motor neurons leads to an increase in the amplitude of the excitatory post‐synaptic potential through its GEF activity. Our results demonstrate that msec7‐1 regulates neuritogenesis and synaptic transmission.
Up‐regulation of cerebral carbonic anhydrase by anoxic stress in piglets
Authors: Nógrádi Antal , Domoki Ferenc , Dégi Rózsa , Borda Stefánia , Pákáski Magdolna , Szabó András , Bari Ferenc 
Published: July 2010

AbstractThe resuscitation of asphyxiated babies is associated with changes in cerebral protein synthesis that can influence the neurological outcome. Insufficient gas exchange results in rapid shifts in extracellular and intracellular pH. Carbonic anhydrase (CA) plays an important role in buffering acute changes in pH in the brain. We investigated whether asphyxia/re‐ventilation influences the expression of cerebral CA isoforms (CA‐II, CA‐III and CA‐IV) in anaesthetized newborn pigs. The cerebral cortex, hippocampus, cerebellum and retina were sampled, and prepared for either CA immunohistochemistry or CA immunoblotting from piglets subjected to asphyxia (10 min) followed by 2–4 h of re‐ventilation, and also from normoxic controls. The CA immunoreactivity (IR) of all the isoforms studied was weak in the controls, apart from staining of a few oligodendrocytes in the subcortical white matter, some astrocytes in the superficial layer of the cerebral cortex, the cerebellar Purkinje cells and the retinal Müller cells that possessed moderate CA‐II IR. However, asphyxia induced a marked increase in the CA IR of all isoforms in all the cerebral regions investigated and the retina after 4 h of survival. The pyramidal cells of the frontal cortex and hippocampus displayed the most conspicuous increase in CA IR. Immunoblotting confirmed increased levels of all the CA isoenzymes. We conclude that raised CA levels after asphyxia may contribute to the compensatory mechanisms that protect against the pathological changes in the neonatal CNS.
Immortalized olfactory ensheathing glia promote axonal regeneration of rat retinal ganglion neurons
Authors: Moreno‐Flores M. Teresa , Lim Filip , Martín‐Bermejo M. Jesús , Díaz‐Nido Javier , Ávila Jesús , Wandosell Francisco 
Published: July 2010

AbstractOlfactory bulb ensheathing glia (OEG) have attracted special attention during the last few years because of their unique properties in promoting regeneration of adult mammalian central nervous system (CNS) components. However the molecular and cellular characteristics responsible for this capacity remain to be revealed. Such studies are presently hindered by the lack of a plentiful source of homogenous OEG. Thus the availability of immortalized OEG lines maintaining the regenerative characteristics of the primary cultures would represent an unlimited source of OEG for use not only in biochemical analyses of neuroregenerative mechanisms but also to characterize their regenerative properties in models in culture and in vivo. We have immortalized primary rat OEG using the SV40 large T antigen expressed from a constitutive cellular promotor, and report here the isolation and characterization of clonal lines. These OEG clonal lines were comparable to primary OEG and Schwann cells in the promotion of axonal regeneration of mature rat retinal ganglion neurons (RGN) but, significantly, this culture assay system more closely reflects the in vivo reparative properties of OEG on transected nerves than other assays of neuritogenesis in that it revealed OEG cells to promote the growth of a larger number of long axons than Schwann cells. Using this assay we were able to grade our OEG lines for their neuroregenerative capacity, opening the possibility of identifying molecules with correlative expression levels in these cells. Our preliminary characterization revealed that the expression level of a classical OEG marker, the p75‐NGF receptor, does not correlate with neuroregenerative capacity.
Efficient gene transfer from innervated muscle into rat peripheral and central nervous systems using a non‐viral haemagglutinating virus of Japan (HVJ)‐liposome method
Authors: Kato Naoki , Nakanishi Kuniaki , Nemoto Koichi , Morishita Ryuichi , Kaneda Yasufumi , Uenoyama Maki , Ikeda Tomosumi , Fujikawa Kyosuke 
Published: July 2010

AbstractWe evaluated the feasibility of gene delivery into the peripheral and central nervous systems via retrograde axonal transport following injection of a haemagglutinating virus of Japan (HVJ)‐liposome‐DNA complex vector into an innervated muscle. Transfection efficiency was assessed by measuring luciferase activity, and was compared statistically with that achieved using a liposome‐DNA control vector. High luciferase activity was observed in the injected muscle, the ipsilateral sciatic nerve, and the ipsilateral dorsal root ganglia on day 1 after gene transfer. The spinal cord also showed luciferase activity, although this was lower than in the other tissues. However, no activity was observed in the contralateral sciatic nerve or the contralateral dorsal root ganglia. In addition, we performed gene transfer twice, with a 1‐week interval, to evaluate the feasibility of repeated therapeutic gene delivery. Again, a high transfection efficiency was observed immediately, even after the second gene transfer, and transfection efficiency was significantly higher at each defined time‐point using the HVJ‐liposome complex vector than using a control vector. These results indicate that this method could be used for repeated therapeutic gene delivery into muscle, nerve, dorsal root ganglia, and possibly spinal cord, without the need for a surgical approach, making it well suited to clinical applications.
Presynaptic control of striatal dopamine neurotransmission in adult vesicular monoamine transporter 2 (VMAT2) mutant mice
Authors: Patel Jyoti , Mooslehner Katrin A. , Chan Pok Man , Emson Piers C. , Stamford Jonathan A. 
Published: July 2010

AbstractThe vesicular monoamine transporter 2 (VMAT2) plays a pivotal role in regulating the size of vesicular and cytosolic dopamine (DA) storage pools within the CNS, and can thus influence extracellular DA neurotransmission. Transgenic mice have been generated with a dramatically reduced (by ∼95%) expression of the VMAT2 gene which, unlike complete knockout lines, survive into adulthood. We compared the pre‐synaptic regulation of both impulse‐dependent (exocytotic) and carrier‐mediated (via reversal of the DA transporter, DAT) DA release in the dorsolateral caudate putamen (CPu) of striatal slices derived from adult homozygous VMAT2 mutant and wild‐type mice using fast cyclic voltammetry. Impulse‐dependent DA release, evoked by a single electrical pulse, was lower in homozygous (116 nm) than wild‐type mice (351 nm) indicating smaller vesicular DA stores, an observation supported by the evanescent effect of amfonelic acid (300 nm) in homozygous mice. Amphetamine (2 μm) increased extracellular DA via DAT reversal in both wild‐type (by 459 nm) and VMAT2 mutant (by 168 nm,p < 0.01 vs. wild‐type) mice. In both cases, the effect was blocked by the DAT inhibitor GBR12935 (1 μm). Simultaneously, amphetamine decreased impulse‐dependent DA release, albeit less in homozygous (by 55%) than in wild‐type (by 78%) mice. In wild‐types, this decrement was largely reversed by GBR12935 but not by the D2/D3 autoreceptor antagonist (–)sulpiride (1 μm). Conversely, in homozygous VMAT2 mutant mice, it was attenuated by (–)sulpiride but not GBR12935. The D2/D3 receptor agonist quinpirole inhibited impulse‐dependent DA release with a lower EC50value in homozygous mice (12 nm) compared with wild‐types (34 nm), indicating the compensatory presence of functionally supersensitive release‐regulating autoreceptors. However, analysis of DA reuptake kinetics obtained in the absence and presence of DAT blockade (by cocaine and amfonelic acid) revealed only minor differences in DAT functionality. These results demonstrate that impaired vesicular DA storage constrains extracellular DA levels in the dorsolateral CPu whether induced by either impulse‐dependent or carrier‐mediated mechanisms and that the relative importance of the DAT and terminal autoreceptors as control mechanisms in the actions of amphetamine are reversed in VMAT2 mutant mice.
Amyloid precursor protein‐processing products affect mononuclear phagocyte activation: pathways for sAPP‐ and Aβ‐mediated neurotoxicity
Authors: Ikezu Tsuneya , Luo Xiaoguang , Weber Gregory A. , Zhao Jianxing , McCabe Laura , Buescher James L. , Ghorpade Anuja , Zheng Jialin , Xiong Huangui 
Published: July 2010

AbstractIncreasing evidence strongly supports the role of glial immunity in the pathogenesis of Alzheimer's disease (AD). To investigate such events we have developed cell systems mimicking the interactions between β‐amyloid precursor protein (APP)‐expressing neurons and brain mononuclear phagocytes (MP; macrophages and microglia). MP were co‐cultured with neuronal cells expressing wild type APP or familial AD‐linked APP mutants. The latter was derived from recombinant adenoviral constructs. Neuronal APP processing products induced MP activation, reactive oxygen species, and neurotoxic activities. These occurred without the addition of pro‐inflammatory cytokines and were reversed by depletion of amyloid β‐peptide (Aβ) and secreted APP (sAPP). Neurotoxic activities were diminished by superoxide dismutase mimetics and NMDA receptor inhibitors. Microglial glutamate secretion was suppressed by the cystine‐glutamate antiporter inhibitor and its levels paralleled the depletion of sAPP and Aβ from conditioned media prepared from APP‐expressing neurons. The excitotoxins from activated MP were potent enough to evoke recombinant NMDA receptor‐mediated inward currents expressed in vitro in the Xenopus oocytes. These results demonstrate that neuronal APP‐processing products can induce oxidative neurotoxicity through microglial activation.