bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential role of the nitric oxide pathway on Δ9‐THC‐induced central nervous system effects in the mouse
Authors: Azad Shahnaz Christina , Marsicano Giovanni , Eberlein Irina , Putzke Jörg , Zieglgänsberger Walter , Spanagel Rainer , Lutz Beat 
Published: March 2003

AbstractThis study investigated whether the nitric oxide pathway was involved in the central effects of Δ9‐tetrahydrocannabinol (Δ9‐THC), the major psychoactive constituent of cannabis sativa. Body temperature, nociception and locomotion were measured in neuronal nitric oxide synthase (nNOS) knock‐out (KO) mice and wild‐type (WT) controls after intraperitoneal application of Δ9‐THC. These Δ9‐THC‐induced effects are known to be mediated through the brain‐type cannabinoid receptor 1 (CB1). Therefore, in situ hybridization (ISH) experiments were performed in the adult murine brain to determine possible changes in CB1 mRNA levels in nNOS‐KO, compared with WT mice, and to reveal brain areas where CB1 and nNOS were coexpressed in the same neurons. We found that an intraperitoneal injection of 10 mg/kg Δ9‐THC led to the same increase in the hot plate latencies in both genotypes, suggesting that Δ9‐THC‐mediated antinociception does not involve nNOS. In contrast, a significant Δ9‐THC‐induced decrease of body temperature and locomotor activity was only observed in WT, but not in nNOS‐KO mice. ISH revealed significantly lower levels of CB1 mRNA in the ventromedial hypothalamus (VMH) and the caudate putamen (Cpu) of the nNOS‐KO animals, compared with WT mice. Both areas are known to be among the regions involved in cannabinoid‐induced thermoregulation and decrease of locomotion. A numerical evaluation of nNOS/CB1 coexpression showed that approximately half of the nNOS‐positive cells in the dorsolateral Cpu also express low levels of CB1. ISH of adjacent serial sections with CB1 and nNOS, revealed expression of both transcripts in VMH, suggesting that numerous nNOS‐positive cells of VMH coexpress CB1. Our findings indicate that the nitric oxide pathway is involved in some, but not all of the central effects of Δ9‐THC.
Enhanced CREB phosphorylation in immature dentate gyrus granule cells precedes neurotrophin expression and indicates a specific role of CREB in granule cell differentiation
Authors: Bender R. A. , Lauterborn J. C. , Gall C. M. , Cariaga W. , Baram T. Z. 
Published: March 2003

AbstractDifferentiation and maturation of dentate gyrus granule cells requires coordinated interactions of numerous processes. These must be regulated by protein factors capable of integrating signals mediated through diverse signalling pathways. Such integrators of inter and intracellular physiological stimuli include the cAMP‐response element binding protein (CREB), a leucine‐zipper class transcription factor that is activated through phosphorylation. Neuronal activity and neurotrophic factors, known to be involved in granule cell differentiation, are major physiologic regulators of CREB function. To examine whether CREB may play a role in governing coordinated gene transcription during granule cell differentiation, we determined the spatial and temporal profiles of phosphorylated (activated) CREB throughout postnatal development in immature rat hippocampus. We demonstrate that CREB activation is confined to discrete, early stages of granule cell differentiation. In addition, CREB phosphorylation occurs prior to expression of the neurotrophins BDNF and NT‐3. These data indicate that in a signal transduction cascade connecting CREB and neurotrophins in the process of granule cell maturation, CREB is located upstream of neurotrophins. Importantly, CREB may be a critical component of the machinery regulating the coordinated transcription of genes contributing to the differentiation of granule cells and their integration into the dentate gyrus network.
Influence of glucocorticoids on dopaminergic transmission in the rat dorsolateral striatum
Authors: Barrot Michel , Abrous Djoher Nora , Marinelli Michela , Rougé‐Pont Françoise , Le Moal Michel , Piazza Pier Vincenzo 
Published: March 2003

AbstractGlucocorticoid hormones exert strong influences on central neurotransmitter systems. In the present work, we examined the functional consequences of corticosterone suppression on the dopaminergic transmission in the dorsolateral striatum by studying the expression of Fos‐like proteins and extracellular dopamine levels. Glucocorticoid hormones were suppressed by adrenalectomy, and the specificity of the effects assessed by restoring physiological plasmatic corticosterone concentrations. We show that, in the dorsolateral striatum, glucocorticoids modify postsynaptic dopaminergic transmission. Suppression of glucocorticoids decreased the induction of Fos proteins in response to a direct agonist of dopamine D1 receptors (SKF 82958, 1.5 mg/kg, i.p.), but not the release of dopamine induced by morphine (2 mg/kg, s.c.) or the density of the limiting enzyme of dopamine synthesis, tyrosine hydroxylase. In contrast to the dopaminergic response to morphine, the response to cocaine (15 mg/kg, i.p.) was modified by the suppression of corticosterone. In this case, adrenalectomy increased cocaine‐induced changes in extracellular dopamine but did not modify the expression of Fos‐like proteins. This absence of changes in cocaine‐induced Fos‐like proteins might result from a compensatory mechanism between the increase in the dopaminergic response and the decrease in the functional activity of dopamine D1 receptors. The increased dopaminergic response to cocaine also contrasts with the decreased response previously observed in the shell of the nucleus accumbens [Barrot et al. (2000) Eur. J. Neurosci., 12, 973–979]. The present data highlight the profound heterogeneous influence of glucocorticoids within dopaminergic projections.
Immunohistochemical localization of voltage‐gated calcium channels in substantia nigra dopamine neurons
Authors: Takada M. , Kang Y. , Imanishi M. 
Published: March 2003

AbstractThe rhythmic firing of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) is thought to be mediated by nifedipine‐sensitive Ca2+channels, although an involvement of ω‐conotoxin‐sensitive Ca2+channels is also suggested. In an attempt to localize such Ca2+channels at both the regional and cellular levels, their expression and distribution patterns were immunohistochemically investigated in the rat SNc. The three distinct subtypes of voltage‐gated Ca2+channels were tested: the class B N‐type α1 subunit (CNB1), the class C L‐type α1 subunit (CNC1) and the class D L‐type α1 subunit (CND1). A large number of SNc neurons showed intense immunoreactivity against CND1 and they were distributed throughout the entire extent. By contrast, many fewer neurons displayed less intense CNC1 immunoreactivity and many of them were located in the lateral aspect of the SNc. No immunoreactivity against CNB1 was detected in the SNc. Moreover, double immunofluorescence analysis in combination with tyrosine hydroxylase staining revealed that virtually all DA neurons were CND1‐immunoreactive whereas many DA neurons especially in the medial SNc exhibited only faint or no immunoreactivity against CNC1. Both CNC1 and CND1 were expressed in cell bodies and proximal dendrites of SNc DA neurons, whilst their distal dendrites that penetrated into the substantia nigra pars reticulata expressed CND1 alone. Thus, the ubiquitously and intensely expressed class D α1 subunit of L‐type Ca2+channels that is sensitive to both nifedipine and ω‐conotoxin may be responsible for the pacemaker activity of SNc DA neurons.
Bcl‐2 overexpression per se does not promote regeneration of neonatal crushed optic fibers
Authors: Lodovichi Claudia , Di Cristo Graziella , Cenni Maria Cristina , Maffei Lamberto 
Published: March 2003

AbstractWe have explored whether overexpression of the bcl‐2gene ‘per se’ can promote regeneration of retinal ganglion cells (RGCs) after optic nerve axotomy in developing transgenic mice. We have used newborn mice (postnatal day 5) because at this age the central nervous system environment is more permissive for regeneration than in adults, thus, maximizing the probability to detect a regeneration‐promoting role of bcl‐2. Thirty days postsurgery we found that in mice overexpressing bcl‐2, a high proportion of retinal ganglion cells survived and also that some fibers in the proximal stump of the optic nerve were preserved. However, the optic nerve of transgenic mice does not show signs of regeneration. On the contrary, in the presence of Schwann cell transplants, there are signs of fiber regrowth. Indeed, many axonal terminals cross the crush site and reach the chiasm in both wild type and transgenic mice nerves. These results suggest that bcl‐2 overexpression is not sufficient ‘per se’ to increase the regenerative potentiality of axotomized RGCs.
The supramammillary nucleus contributes to associative EPSP‐spike potentiation in the rat dentate gyrus in vivo
Authors: Nakanishi Kosuke , Saito Hiroshi , Abe Kazuho 
Published: March 2003

AbstractThe supramammillary nucleus (SUM) of the hypothalamus sends neural projections to the hippocampus and is supposed to be involved in learning and memory. To test the possibility that SUM afferents modulate hippocampal functions, we investigated the effect of electrical stimulation of the SUM on the induction of long‐term potentiation (LTP) at medial perforant path (PP)–granule cell synapses in the dentate gyrus (DG) of anaesthetized rats. High‐frequency stimulation of the SUM (100 pulses at 100 Hz) alone did not change PP–DG field potentials. However, when the SUM stimulation was applied simultaneously with weak tetanic stimulation of the PP (20 pulses at 20 Hz) which alone did not induce any potentiation, it produced a long‐lasting potentiation of the population spike, without an accompanying increase in the population excitatory postsynaptic potential (EPSP). The EPSP‐spike (E‐S) potentiation induced by pairing SUM and PP stimulation was abolished by lesions of the fimbria–fornix, a major pathway of SUM afferents. SUM stimulation applied 1 s before or after PP stimulation failed to produce E‐S potentiation, and SUM stimulation augmented PP–DG field potentials during tetanic stimulation. Furthermore, the E‐S potentiation was abolished by blocking GABAergic neurotransmission with picrotoxin. These results suggest that coactivation of SUM and PP inputs produces a long‐lasting increase of granule cell excitability by modulating GABAergic inhibition. SUM afferents may contribute to associative memory processing by modulating hippocampal excitability.
Role of GAP‐43 in mediating the responsiveness of cerebellar and precerebellar neurons to axotomy
Authors: Wehrlé Rosine , Caroni Pico , Sotelo Constantino , Dusart Isabelle 
Published: March 2003

AbstractTo determine whether the competence for axonal sprouting and/or regeneration in the cerebellar system correlates with GAP‐43 expression, we have studied GAP‐43 mRNA and protein expression in the postlesioned cerebellum and inferior olive. Purkinje cells transiently express GAP‐43 during their developmental phase (from E15 to P5 in the rat) which consists of fast axonal growth and the formation of the corticonuclear projection. Adult Purkinje cells, which in control adult rats do not express GAP‐43, are extremely resistant to the effects of axotomy but cannot regenerate axons. However, a late and protracted sprouting of axotomized Purkinje cells occurs spontaneously and correlates with a mild expression of GAP‐43 mRNA. In contrast, inferior olivary neurons, despite their high constitutive expression of GAP‐43, do not sprout but retract their axons and die after axotomy. Furthermore, mature Purkinje cells in cerebellar explants of transgenic mice that overexpress GAP‐43 do not regenerate after axotomy, even in the presence of a permissive substrate (cerebellar embryonic tissue) and, contrary to the case in wild‐type mice, they do not survive in the in vitro conditions and undergo massive cell death. These results show that the expression of GAP‐43 is not only associated with axonal growth, but also with neuronal death.
The D2 receptor is critical in mediating opiate motivation only in opiate‐dependent and withdrawn mice
Authors: Dockstader Colleen L. , Rubinstein Marcelo , Grandy David K. , Low Malcolm J. , Van Der Kooy Derek 
Published: March 2003

AbstractAccording to the dual systems model for opiate reward, dopamine mediates opiate motivation when an animal is in a deprived motivational state (i.e. opiate‐dependent and in withdrawal) and not when an animal is in a nondeprived state (i.e. previously drug‐naive). To determine the role of the D2 dopamine receptor subtype in mediating opiate motivation, we examined the behaviour of N5 congenic D2 receptor knockout mice and their wild‐type siblings in opiate‐naive and opiate‐dependent and withdrawn place conditioning paradigms. Opiate‐naive D2 receptor knockout mice demonstrated acquisition of morphine‐conditioned place preference but failed to acquire place preference when conditioned in the deprived state. We propose that D2 receptor function is critical in mediating the motivational effects of opiates only when the animal is in an opiate‐dependent and withdrawn motivational state. These findings also underscore the important influence of the genetic background to a given phenotype, as evidenced by the observation that increasing the allelic contribution from the 129/SvJ strain abolishes morphine place preference in C57BL/6 wild‐type mice.
GABAA receptors in the ventral tegmental area control bidirectional reward signalling between dopaminergic and non‐dopaminergic neural motivational systems
Authors: Laviolette Steven R. , Van Der Kooy Derek 
Published: March 2003

AbstractIn the midbrain ventral tegmental area (VTA), both dopaminergic and nondopaminergic neural substrates mediate various behavioural reward phenomena. VTA GABAergic neurons are anatomically positioned to influence the activity of both the mesolimbic dopamine system and nondopamine efferents from the VTA. In order to examine the possible functional role of VTA GABAA receptors in neural reward processes, we performed discrete, bilateral microinjections of the GABAA receptor agonist, muscimol, or the GABAA receptor antagonist, bicuculline, into the VTA. Using a fully counterbalanced, unbiased conditioned place‐preference paradigm, we demonstrate that activation of VTA GABAA receptors, with the GABAA receptor agonist muscimol (5–50 ng/µL), or inhibition of VTA GABAA receptors, with the GABAA receptor antagonist bicuculline (5–50 ng/µL), both produce robust rewarding effects. Furthermore, these rewarding effects can be pharmacologically dissociated: blockade of dopamine receptors with a dopamine receptor antagonist, α‐flupenthixol (0.8 mg/kg; i.p.), or concurrent activation of VTA GABAB receptors with a GABAB receptor agonist, baclofen (70 ng/µL), blocked the rewarding properties of the GABAA receptor agonist, but had no effect on the rewarding properties of the GABAA receptor antagonist. These results suggest that, within the VTA, a single GABAA receptor substrate controls bidirectional reward signalling between dopaminergic and nondopaminergic brain reward systems.
P2Y receptor‐mediated inhibition of voltage‐activated Ca2+ currents in PC12 cells
Authors: Vartian Nina , Boehm Stefan 
Published: March 2003

AbstractTo search for inhibitory nucleotide receptors in the sympathoadrenal cell lineage of the rat, voltage‐activated Ca2+ currents were recorded in PC12 cells after differentiation with nerve growth factor. ADP and ATP, but not uridine nucleotides, reduced Ca2+ current amplitudes and slowed activation kinetics. This effect was mediated by GTP binding proteins, as it was abolished by intracellular GDPβS and after treatment with pertussis toxin. Furthermore, depolarizations preceding the activation of Ca2+ currents abolished the ADP‐induced slowing of activation kinetics and attenuated its inhibitory action on current amplitudes. The modulatory effect of ADP was neither altered in the presence of adenosine receptor antagonists, nor mimicked by agonists at these receptors. In addition, the action of ADP was antagonized by reactive blue 2, but not by suramin or PPADS. Nucleotides tested for their inhibitory action on Ca2+ currents displayed the following rank order of potency: 2‐methylthio‐ADP ≥ 2‐methylthio‐ATP >> ADPβS > ADP = ATP. When P2X receptors were blocked, the P2X agonists ATP and 2‐methylthio‐ATP still reduced Ca2+ currents. The P2Y1 receptor antagonists adenosine‐2’‐phosphate‐5’‐phosphate and adenosine‐3’‐phosphate‐5’‐phosphate did not alter the inhibitory action of ADP, whereas the Sp‐isomer of adenosine‐5’‐O‐(1‐thiotriphosphate) and 2’‐ and 3’‐O‐(4‐benzoylbenzoyl)‐ATP showed significant antagonistic activity. These results demonstrate that PC12 cells express an as yet unidentified P2Y receptor with pharmacological characteristics similar to those of P2Y1. As receptor‐dependent modulation of Ca2+ channels is a key event in presynaptic inhibition, this receptor may correspond to previously described presynaptic nucleotide receptors mediating autoinhibition of sympathetic transmitter release.
Adrenoreceptor‐mediated modulation of the spinal locomotor pattern during swimming in Xenopus laevis tadpoles
Authors: Fischer Hanno , Merrywest Simon D. , Sillar Keith T. 
Published: March 2003

AbstractThis study focused on the contribution of different adrenoreceptor subtypes to the modulation of fictive swimming activity in a relatively simple, yet intact, lower vertebrate system, the immobilized Xenopus laevis tadpole and explored their possible role in mediating the noradrenergic modulation of spinal motor networks. In Xenopus embryos, near the time of hatching, activation of α1 adrenoreceptors increased the duration of episodes of fictive swimming, whilst in larvae, 24 h after hatching, they were decreased. Activation of α2 adrenoreceptors, however, markedly reduced episode duration at both developmental stages. Cycle periods in both stages were increased by the activation of α1 and/or α2 receptor subclasses, whereas β adrenoreceptors were not apparently involved in the modulation of cycle periods or the duration of swim episodes. However, both β and α1 receptor activation decreased the intersegmental delay in the head‐to‐tail propagation of swimming activity, while α2 receptors did not influence these rostro‐caudal delays. Activation of neither α, nor β, receptor subclasses had any consistent effect on the duration of ventral motor bursts. Our findings suggest that noradrenergic modulation of the swim‐pattern generator in Xenopus tadpoles is mediated through the activation of α and β adrenoreceptors. In addition, activation of particular receptor subclasses might enable the selective modulation of either the segmental rhythm generating networks, the intersegmental coordination of those networks or control at both levels simultaneously.
Photoreceptor plasticity in reaggregates of embryonic chick retina: rods depend on proximal cones and on tissue organization
Authors: Rothermel Andrée , Layer Paul G. 
Published: March 2003

AbstractPlasticity of photoreceptors and their integration into epithelial structures homologous to an outer nuclear layer (ONL), was investigated in embryonic chick retinal cell reaggregates by immunohistochemistry using an antibody specific for red plus green cones (RG‐cones) and an antibody for rods. If reaggregates are raised in the presence of pigmented epithelium (RPE), completely reconstructed, stratified retinal spheres are produced, where all rods and cones are integrated into an outer laminar ONL, similar to a normal retina. In the absence of RPE, ‘rosetted’ spheres form which contain internal rosettes homologous to an ONL. Only a minor fraction of cones and rods of ‘rosetted’ spheres are located within rosettes, while a larger fraction is diffusely displaced in nonorganized areas, thus, not contributing to an ONL‐like epithelium. In both types of spheres, the total percentage of RG‐cones was similar to the in vivo retina, indicating that expression of cones is autonomous. Following cones, after about one day, rods developed only within already existing RG‐cone clusters. Thereby, the ratio of rods to RG‐cones increases as the tissue organization decreases: for stratified spheres this ratio is, 0.50 (1 rod/2 cones; similar to mature retina); for rosettes, 0.74 (3 rods/4 cones) and for nonorganized areas, 1.09 (1 rod/1 cone) – a higher ratio under our conditions has never been detected. Thus, rod expression depends strictly on the presence of nearby cones; their relative numbers are distinctively adjusted according to the cytoarchitecture of the tissue environment. The biomedical implications of these findings are briefly discussed.
Effects of amyloid peptides on cell viability and expression of neuropeptides in cultured rat dorsal root ganglion neurons: a role for free radicals and protein kinase C
Authors: Ma Weiya , Zheng Wen‐Hua , Belanger Serge , Kar Satyabrata , Quirion Remi 
Published: March 2003

AbstractChronic pain caused by nerve injury and inflammation is more common in the elderly. However, mechanisms underlying this phenomenon are unclear. Higher sensitivity of sensory neurons to free radicals has been suggested as one possibility. The production of free radicals can be induced by various agents, including the highly toxic protein β‐amyloid (Aβ), which is found in higher amounts in the brains of Alzheimer's Disease patients. In dorsal root ganglion (DRG) cultures exposed to Aβ, we examined cellular toxicity and peptide expression, in particular calcitonin gene‐related peptide (CGRP), a peptide which is abundantly expressed by nociceptive afferents and is known to be involved in pain processes. Exposure of cultured rat DRG neurons to Aβ25−35 or Aβ1−40 (10 or 20 µm for 24–96 h) increased trypan blue‐stained cells in a concentration‐ and time‐dependent manner, thus, indicating cellular toxicity. These treatments also increased the number of CGRP immunoreactive (IR) neurons while decreasing the number of neuropeptide Y‐ and galanin‐IR neurons. The free radical scavenger, superoxide dismutase, attenuated both the toxicity and neuropeptide changes induced by Aβ, thus, suggesting that oxidative stress probably contributes to these effects. Exposure of cultured DRG neurons to Aβ also increased the number of protein kinase Cα (PKCα)‐IR neurons. The PKC inhibitors, chelerythrine chloride and Gö6976, significantly augmented Aβ‐induced cellular toxicity while attenuating the increases in CGRP‐and PKCα‐IR cells, supporting the notion of a protective role for PKC in Aβ insults. These in vitro data suggest that Aβ peptides may, in addition to causing neurotoxicity, regulate neuropeptide expression in primary afferents. This finding could be relevant to the higher incidence of neuropathic pain that occurs with ageing.