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  • 1
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Shaker K+ channels play an important role in modulating electrical excitability of axons. Recent work has demonstrated that the T1 tetramerization domain of Kv1.2 is both necessary and sufficient for targeting of the channel to the axonal surface [Gu, C., Jan, Y.N. & Jan, L.Y. (2003)Science,301, 646–649]. Here we use a related channel, Kv1.3, as a model to investigate cellular mechanisms that mediate axonal targeting. We show that the T1 domain of Kv1.3 is necessary and sufficient to mediate targeting of the channel to the axonal surface in pyramidal neurons in slices of cortex from neonatal rat. The T1 domain is also sufficient to cause preferential axonal localization of intracellular protein, which indicates that the domain probably does not work through compartment-specific endocytosis or compartment-specific vesicle docking. To determine whether the T1 domain mediates axonal trafficking of transport vesicles, we compared the trafficking of vesicles containing green fluorescent protein-labelled transferrin receptor with those containing the same protein fused with the T1 domain in living cortical neurons. Vesicles containing the wild-type transferrin receptor did not traffic to the axon, in accord with previously published results; however, those containing the transferrin receptor fused to T1 did traffic to the axon. These results are consistent with the T1 domain of Kv1.3 mediating axonal targeting by causing transport vesicles to traffic to axons and they represent the first evidence that such a mechanism might underlie axonal targeting.
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  • 2
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Adult hippocampal neurogenesis is enhanced in response to multiple stimuli including seizures. However, the relationship between neurogenesis and the development of temporal lobe epilepsy (TLE) remains unclear. Unilateral intrahippocampal injection of kainate in adult mice models the morphological characteristics (e.g. neuronal loss, gliosis, granule cell dispersion and hypertrophy) and occurrence of chronic, spontaneous recurrent partial seizures observed in human TLE. We investigated the influence of a kainate-induced epileptogenic focus on hippocampal neurogenesis, comparing neural stem cell proliferation following status epilepticus and spontaneous recurrent partial seizures. Cell proliferation in the subgranular zone was transiently increased bilaterally after kainate treatment. As a result, neurogenesis was stimulated in the contralateral dentate gyrus. In contrast, the epileptic hippocampus exhibited a strongly reduced neurogenic potential, even after onset of spontaneous recurrent partial seizures, possibly due to an alteration of the neurogenic niche in the subgranular zone. These results show that neurogenesis does not contribute to the formation of the epileptic focus and may be affected when dispersion of dentate gyrus granule cells occurs. Therefore, in patients with TLE, hippocampal sclerosis and granule cell dispersion may play a significant role in disrupting the potential for hippocampal neurogenesis.
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  • 3
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Among the well-established roles of the neurotransmitter histamine (HA) is that as a regulator of the sleep–wake cycle, which early gained HA a reputation as a ‘waking substance’. The tuberomammillary nucleus (TMN) of the posterior hypothalamus, which contains the sole source of neuronal HA in the brain, is reciprocally connected to the suprachiasmatic nucleus (SCN) which, in turn, is best known as the pacemaker of circadian rhythms in mammals. We report HA-immunoreactive (-ir) neurons in the mouse and rat SCN that neither display immunoreactivity (-iry) for the HA-synthesizing enzyme histidine decarboxylase (HDC) nor contain HDC mRNA. Further, HA-iry was absent in the SCN of HDC knockout mice, but present in appropriate control animals, indicating that the observed HA-iry is HDC dependent. Experiments with hypothalamic slice cultures and i.c.v. injection of HA suggest that HA in the SCN neurons originates in the TMN and is transported from the TMN along histaminergic fibres known to innervate the SCN. These results could indicate the existence of a hitherto unknown uptake mechanism for HA into neurons. Through HA uptake and, putatively, re-release of the captured HA, these neurons could participate in the HA-mediated effects on the circadian system in concert with direct histaminergic inputs from the TMN to the SCN. The innervation of the SCN by several neurotransmitter systems could provide a way for other systems to affect the HA-containing neuronal cell bodies in the SCN.
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  • 4
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: We compared image computation in the rabbit retina by two different cell types: the so-called ‘local edge detecting’ ganglion cells and the well-known brisk–sustained ganglion cells. From both anatomical and physiological evidence, these cells are present in nearly equal numbers and thus overlap to sample the same regions of visual space. We recorded simultaneously from overlapping cells on a dense microelectrode array. The results were analysed using an anatomically realistic simulation of the retina's processing levels. The ‘local edge detecting’ cell was found to be tuned to higher spatial frequencies and to have a narrower spatial frequency bandpass than the brisk–sustained cells. Simulation revealed that this is due primarily to the ‘zero-crossing’ detector implied by the definition of the local edge detector. The outputs of the simulations in response to complex images were analysed quantitatively. The results showed the population of local edge detectors to transmit a sparser code than the brisk–sustained cells.
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  • 5
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: To obtain insight into the morphological and molecular correlates of motoneuron degeneration in amyotrophic lateral sclerosis (ALS) mice that express G93A mutant superoxide dismutase (SOD)1 (G93A mice), we have mapped and characterized ‘sick’ motoneurons labelled by the ‘stress transcription factors’ ATF3 and phospho-c-Jun. Immunocytochemistry and in situ hybridization showed that a subset of motoneurons express ATF3 from a relatively early phase of disease before the onset of active caspase 3 expression and motoneuron loss. The highest number of ATF3-expressing motoneurons occurred at symptom onset. The onset of ATF3 expression correlated with the appearance of ubiquitinated neurites. Confocal double-labelling immunofluorescence showed that all ATF3-positive motoneurons were immunoreactive for phosphorylated c-Jun. Furthermore, the majority of ATF3 and phospho-c-Jun-positive motoneurons were also immunoreactive for CHOP (GADD153) and showed Golgi fragmentation. A subset of ATF3 and phosphorylated c-Jun-immunoreactive motoneurons showed an abnormal appearance characterized by a number of distinctive features, including an eccentric flattened nucleus, perikaryal accumulation of ubiquitin immunoreactivity, juxta-nuclear accumulation of the Golgi apparatus and the endoplasmic reticulum, and intense Hsp70 immunoreactivity. These abnormal cells were not immunoreactive for active caspase 3. We conclude that motoneurons in ALS-SOD1 mice prior to their death and disappearance experience a prolonged sick phase, characterized by the gradual accumulation of ubiquitinated material first in the neurites and subsequently the cell body.
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  • 6
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abnormal hyperphosphorylation of tau is believed to lead to neurofibrillary degeneration in Alzheimer's disease (AD) and other tauopathies. Recent studies have shown that protein phosphatases (PPs) PP1, PP2A, PP2B and PP5 dephosphorylate tau in vitro, but the exact role of each of these phosphatases in the regulation of site-specific phosphorylation of tau in the human brain was unknown. Hence, we investigated the contributions of these PPs to the regulation of tau phosphorylation quantitatively. We found that these four phosphatases all dephosphorylated tau at Ser199, Ser202, Thr205, Thr212, Ser214, Ser235, Ser262, Ser396, Ser404 and Ser409, but with different efficiencies toward different sites. The Km values of tau dephosphorylation catalysed by PP1, PP2A and PP5 were 8–12 µm, similar to the intraneuronal tau concentration of human brain, whereas the Km of PP2B was fivefold higher. PP2A, PP1, PP5 and PP2B accounted for ∼ 71%, ∼ 11%, ∼ 10% and ∼ 7%, respectively, of the total tau phosphatase activity of human brain. The total phosphatase activity and the activities of PP2A and PP5 toward tau were significantly decreased, whereas that of PP2B was increased in AD brain. PP2A activity negatively correlated to the level of tau phosphorylation at the most phosphorylation sites in human brains. Our findings indicate that PP2A is the major tau phosphatase that regulates its phosphorylation at multiple sites in human brain. The abnormal hyperphosphorylation of tau is partially due to a downregulation of PP2A activity in AD brain.
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  • 7
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Synchronous activity of large populations of neurons shapes neuronal networks during development. However, re-emergence of such activity at later stages of development could severely disrupt the orderly processing of sensory information, e.g. in the spinal dorsal horn. We used Ca2+ imaging in spinal cord slices of neonatal and young rats to assess under which conditions synchronous activity occurs in dorsal horn. No spontaneous synchronous Ca2+ transients were detected. However, increasing neuronal excitability by application of 4-aminopyridine after pretreatment of the slice with blockers of (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate, γ-aminobutyric acid (GABA)A and glycine receptors evoked repetitive Ca2+ waves in dorsal horn. These waves spread mediolaterally with a speed of 1.0 ± 0.1 mm/s and affected virtually every dorsal horn neuron. The Ca2+ waves were associated with large depolarizing shifts of the membrane potential of participating neurons and were most likely synaptically mediated because they were abolished by blockade of action potentials or N-methyl-d-aspartate (NMDA) receptors. They were most pronounced in the superficial dorsal horn and absent from the ventral horn. A significant proportion of the Ca2+ waves spread to the contralateral dorsal horn. This seemed to be enabled by disinhibition as primary afferent-induced dorsal horn excitation crossed the midline only when GABAA and glycine receptors were blocked. Interestingly, the Ca2+ waves occurred under conditions where AMPA/kainate receptors were blocked. Thus, superficial dorsal horn NMDA receptors are able to sustain synchronous neuronal excitation in the absence of functional AMPA/kainate receptors.
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  • 8
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Brain-derived neurotrophic factor (BDNF) exerts its trophic effects by acting on the high-affinity specific receptor trkB. BDNF also modulates synaptic transmission in several areas of the CNS, including the spinal cord dorsal horn, where it acts as a pain modulator by yet incompletely understood mechanisms. Spinal neurons are the main source of trkB in lamina II (substantia gelatinosa). Expression of this receptor in dorsal root ganglion (DRG) cells has been a matter of debate, whereas a subpopulation of DRG neurons bears trkA receptors and contains BDNF. By the use of two different trkB antibodies we observed that 7.7% and 10.8% of DRG neurons co-expressed BDNF + trkB but not trkA, respectively, in rat and mouse. Ultrastructurally, full-length trkB (fl-trkB) receptors were present at somato-dendritic membranes of lamina II neurons (rat: 66.8%; mouse: 73.8%) and at axon terminals (rat: 33.2%; mouse: 26.2%). In both species, about 90% of these terminals were identified as primary afferent fibres (PAFs) considering their morphology and/or neuropeptide content. All fl-trkB-immunopositive C boutons in type Ib glomeruli were immunoreactive for BDNF and, at individual glomeruli and axo-dendritic synapses, fl-trkB receptors were located in a mutually exclusive fashion at pre- or postsynaptic membranes. Thus, only a small fraction of fl-trkB-immunoreactive dendrites were postsynaptic to BDNF-immunopositive PAFs. This is the first ultrastructural description of fl-trkB localization at synapses between first- and second-order sensory neurons in lamina II, and suggests that BDNF may be released by fl-trkB-immunopositive PAFs to modulate nociceptive input in this lamina of dorsal horn.
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  • 9
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Our study aimed to identify gray matter volume differences between panic disorder patients and healthy volunteers using optimized voxel-based morphometry. Gray matter volume was compared between 18 panic subjects and 18 healthy volunteers. Panic disorder severity scale (PDSS) and Zung self-rating anxiety scale (Z-SAS) were administered. Gray matter volumes of bilateral putamen were decreased in panic subjects relative to healthy comparison subjects (corrected P 〈 0.05). Decreased gray matter volume was also observed in the right precuneus, right inferior temporal gyrus, right inferior frontal gyrus, left superior temporal gyrus, and left superior frontal gyrus at a less conservative level of significance. PDSS score negatively correlated with gray matter volume in the left putamen, right putamen, right inferior frontal gyrus, and left superior frontal gyrus in panic subjects. The duration of illness negatively correlated with left putaminal gray matter volume. There was also a negative correlation between gray matter volume in right putamen and Z-SAS score in panic subjects. The current study reports a putaminal gray matter volume decrease in panic subjects, which may be related to the clinical severity of panic disorder.
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  • 10
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In the dentate gyrus neurons continue to be generated from late embryonic to adult stage. Recent extensive studies have unveiled several key aspects of the adult neurogenesis, but only few attempts have so far been made on the analysis of the early postnatal neurogenenesis, a transition state between the embryonic and adult neurogenesis. Here, we focus on the early postnatal neurogenesis and examine the nature and development of neural progenitor cells in Wistar rats. Immunohistochemistry for Ki67, a cell cycle marker, and 5-bromo-2-deoxyuridine (BrdU) labelling show that cell proliferation occurs mainly in the hilus and partly in the subgranular zone. A majority of the proliferating cells express S100β and astrocyte-specific glutamate transporter (GLAST) and the subpopulation are also positive for glial fibrillary acidic protein (GFAP) and nestin. Tracing with BrdU and our modified retrovirus vector carrying enhanced green fluorescent protein (GFP) indicate that a substantial population of the proliferating cells differentiate into proliferative neuroblasts and immature neurons in the hilus, which then migrate to the granule cell layer (66.8%), leaving a long axon-like process behind in the hilus, and the others mainly become star-shaped astrocytes (12.0%) and radial glia-like cells (4.7%) in the subgranular zone. These results suggest that the progenitors of the granule cells expressing astrocytic and radial glial markers, proliferate and differentiate into neurons mainly in the hilus during the early postnatal period.
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  • 11
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The two main sources of excitatory input to CA1 pyramidal cells, the Schaffer collaterals (SC) and the perforant path (PP), target different regions of the dendritic tree. This spatial segregation may have important consequences for the way in which different inputs affect the activity of principal neurons. We constructed detailed biophysical models of CA1 pyramidal cells, incorporating a variety of active conductances, and investigated the ability of synapses located in different dendritic segments to elicit a somatic voltage response. Synaptic efficacy as seen by the soma was strongly dependent on the site of the synapse, with PP inputs being more severely attenuated than SC inputs. Variability within SC inputs, but not between SC inputs and PP inputs, could be eliminated by appropriate scaling of synaptic efficacy. The spatial and temporal summation of multiple synaptic inputs was also investigated. While summation of SC inputs was linear up to the somatic spike threshold, PP inputs summed in a strongly sublinear fashion, with the somatic response remaining subthreshold even following the simultaneous activation of a large number of synapses and during stimulation with high-frequency trains. Finally, the relative impact of different pathways on somatic activity could be effectively altered by modulating the kinetic properties of dendritic transient K+ channels, corresponding to the activation of ascending modulatory neurotransmitter systems. In this case, the efficacy of the PP was enhanced by the dendritic generation and limited spread of action potentials. Strong PP activation could also evoke dendritic Ca++ spikes, which often triggered a somatic burst.
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  • 12
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In order to characterize cortical responses to coherent motion we use magnetoencephalography (MEG) to measure human brain activity that is modulated by the degree of global coherence in a visual motion stimulus. Five subjects passively viewed two-phase motion sequences of sparse random dot fields. In the first (incoherent) phase the dots moved in random directions; in the second (coherent) phase a variable percentage of dots moved uniformly in one direction while the others moved randomly. We show that: (i) visual-motion-evoked magnetic fields, measured with a whole-scalp neuromagnetometer, reveal two transient events, within which we identify two significant peaks – the ‘ON-M220’ peak approximately 220 ms after the onset of incoherent motion and the ‘TR-M230’ peak, approximately 230 ms after the transition from incoherent to coherent motion; (ii) in lateral occipital channels, the TR-M230 peak amplitude varies with the percentage of motion coherence; (iii) two main sources are active in response to the transition from incoherent to coherent motion, the human medial temporal area complex/V3 accessory area (hMT+/V3A) and the superior temporal sulcus (STS), and (iv) these distinct areas show a similar, significant dependence of response strength and latency on motion coherence.
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  • 13
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The effect of 5-bromo-2′-deoxyuridine (BrdU) incorporation on the phenotype of progeny derived from expanded E18 rat striatal precursors was examined. BrdU was administered to cultures for 24 h prior to differentiation. Results revealed that there was selective toxicity of this compound to developing TuJ1+ neurons, but not glia, at concentrations used in most labelling studies. Therefore, a BrdU dose–response curve from 0.2 µm to 10 µm was established. The optimum dose of BrdU for labelling cells was 0.2 µm, well below the 1–10 µm recommended concentration. This dose resulted in the survival of significantly more newborn BrdU/TuJ1+ double-labelled neurons and eliminated the toxic effects of BrdU. Administration of 10 µm BrdU resulted in a significant decrease in extracellular regulated kinase (ERK) phosphorylation compared with untreated cultures, this could be completely restored by the administration of either N-methyl-d-aspartate (NMDA) receptor antagonists such as MK801 or the nitric oxide synthesis inhibitor l-methyl-arginine methyl ester (L-NAME). Our results show that high levels of BrdU are selectively toxic to neurons through a mechanism that activates classical cell death pathways. This has implications for labelling studies both in vivo and in vitro.
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  • 14
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Arbitrary visuomotor associations map a stimulus onto a particular response upon reinforcing rewards. Changes in the associations between stimuli and responses require the neural networks to discard the already learned mappings and build new ones. This is a key aspect of cognitive flexibility. In addition, learning within this experimental paradigm requires a trial-and-error exploration strategy of the available stimulus–response associations. A system performing this task must be able to both build up mappings for stimulus–response associations and at the same time perform non-deterministically to explore the behavioural space until it reaches certainty. We hypothesize an integrate-and-fire network model that accounts for the neurophysiological data of a conditional visuomotor association task and is able to show non-deterministic behaviour. We aim at identifying multistable attractor regimes in the network dynamics, which intrinsically enable the system to make errors and thereby to perform trial-and-error exploration. Our model combines cognitive flexibility with multistable attractors in neurodynamical systems, believed to be the basis of decision-making. If multistable attractors support the exploration of the behavioural space, then our model predicts that the brain should respond stochastically with correct or incorrect activity to visuomotor associations until it has reached certainty. This should be visible not only in the corresponding activity in the premotor area, but also in activity corresponding to other associations or even other stimuli in the prefrontal cortex.
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  • 15
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Astrocytes are, as normal constituents of the brain, promising vehicles for ex vivo gene delivery to the central nervous system. In the present study, we have used a lentiviral vector encoding glial cell line-derived neurotrophic factor (GDNF) to transduce rat-derived primary astrocytes, in order to evaluate their potential for long-term transgene expression in vivo and neuroprotection in a rat model of Parkinson's disease. Following transplantation of GDNF-transduced astrocytes to the intact striatum, the level of released GDNF was 2.93 ± 0.28 ng/mg tissue at 1 week post-grafting, reduced to 0.42 ± 0.12 ng/mg tissue at 4 weeks, and thereafter was maintained at this level throughout the experiment (12 weeks; 0.53 ± 0.068 ng/mg tissue). Similarly, grafting to the substantia nigra (SN) resulted in a significant overexpression of GDNF (∼0.20 ng/mg tissue) at 1 week. Intact animals receiving transplants of GDNF-transduced astrocytes displayed an increased contralateral turning (5.39 ± 1.19 turns/min) in the amphetamine-induced rotation test, which significantly correlated with the GDNF tissue levels measured in the striatum, indicating a stimulatory effect of GDNF on the dopaminergic function. Transplantation of GDNF-transduced astrocytes to the SN 1 week prior to an intrastriatal 6-hydroxydopamine lesion provided a significant protection of nigral tyrosine hydroxylase-positive cells. By contrast, when the cells were transplanted to the striatum, the level of released GDNF was not sufficient to rescue the striatal fibers and, hence, to protect the nigral dopaminergic neurons. Overall, our results suggest that genetically modified astrocytes expressing GDNF can provide neuroprotection in a rat model of Parkinson's disease following transplantation to the SN.
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  • 16
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels are involved in the control of neuronal excitability and plasticity. In this study, we used immunoblotting and immunohistochemical techniques to reveal the developmental expression and subcellular distribution of the HCN1 subunit in the cerebellar cortex. During postnatal development, the spatio-temporal expression of HCN1 correlated well with the morphological events occurring during the ontogenesis of cerebellar interneurons. Using immunoblotting techniques, HCN1 was weakly detected during the first postnatal week and continued to increase throughout postnatal development, peaking at postnatal day (P)15. At the light-microscopic level, HCN1 immunoreactivity was very weak until P7 whereas from P10–12 to adulthood it was strongly detected in the lower third of the molecular layer and in the Purkinje cell layer. HCN1 was present in axons running through the molecular layer and in the pericellular basket around Purkinje cells at P12, but in the periaxonal plexus (the pinceau) surrounding their initial segment only after P15. Using immunofluorescence, HCN1 colocalized with GAD65 and synaptophysin, demonstrating that the subunit was present in inhibitory axons and axon terminals. At the electron-microscopic level, in adulthood, HCN1 immunoparticles were detected at postsynaptic sites in basket and Purkinje cells but most immunoparticles were found at presynaptic sites in basket cell axons and in terminals. In the axon terminals, the distribution of HCN1 was relatively uniform along the extrasynaptic plasma membrane; this was confirmed using quantitative techniques. The present findings suggest that HCN1 channels may provide a significant route for modulating co-ordinated cerebellar synaptic transmission through basket cells.
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  • 17
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Evaluating medications in animal laboratory paradigms can reveal whether the compound is effective in an established alcoholism model, at clinically relevant doses and exposure conditions, when administered orally (or transdermally) and without serious limiting side effects. Positive outcomes constitute a possible discovery for relevance to alcoholism and, under favorable marketing conditions, encourage further development. Medication testing using animal models of alcoholism might also guide clinical testing by discriminating clinically effective from clinically ineffective compounds. This ability rests on whether there are tests or, more reasonably, batteries of tests having this discriminative ability. The present paper examines this possibility. Effects of naltrexone and acamprosate in animal paradigms which model behavioral aspects of alcoholism are reviewed and compared with the effects of compounds which have limited effects in alcoholics. It is not clear at present whether any single paradigm or combination of paradigms differentiates clinically effective from clinically limited compounds. Steps are suggested to improve the use of preclinical laboratory tests to predict which compounds are likely to be effective medications for reducing drinking and sustaining abstinence in human alcoholics.
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  • 18
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Recently, two new ecstasy-like substances, methylone and mCPP, were found in street drugs in the Netherlands by the Drugs Information and Monitoring System (DIMS). Methylone (3,4-methylenedioxymethcathinone) is the main ingredient of a new liquid designer drug that appeared on the Dutch drug market, called ‘Explosion’. mCPP (meta-chlorophenylpiperazine) is a substance often used as a probe for the serotonin function in psychiatric research, and has now been found in street drugs, both in tablets and powders. Methylone as well as mCPP act on monoaminergic systems, resembling MDMA (3,4-methylenedioxymethamphetamine), with mCPP mainly affecting the serotonin system. The subjective effects of both new substances exhibit subtle differences with those of MDMA. Only little is known about the harmfulness of both methylone and mCPP. However, because of similarities between these substances and MDMA, risks common to MDMA cannot be excluded.
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  • 19
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Dopaminergic transmission has been suggested to be a main mechanism mediating reinforcement, withdrawal and craving in alcohol dependency. Dopamine is associated with prolactin secretion, acting as a prolactin inhibitor. The aim of the present study was to investigate whether there is an association between altered prolactin levels and craving during early and late alcohol withdrawal. Therefore, we examined 145 patients suffering from alcohol dependency after admission to the detoxification unit, assessing craving with the Obsessive Compulsive Drinking Scale (OCDS) and measuring prolactin serum levels during early withdrawal (-EW: day 0 or day 1) and late withdrawal (-LW: day 7–day 10). We observed a significant influence of the alteration of prolactin during withdrawal on craving in female patients (Spearman's rho, OCDS-EW: r =−0.607, p =0.001; OCDS-LW: r =−0.730, p2 =0.530; OCDS-LW: F =17.091, p2 =0.535). In male patients we did not find any significant results. Our findings support the previously described role of the hypothalamic–pituitary–adrenal (HPA) axis in the neurobiology of alcohol craving and show evidence of an association between increased prolactin serum levels and lower craving during alcohol withdrawal in female patients.
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  • 20
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: As, for ethical reasons, it is difficult to investigate by an experiment the effect of acute intoxication on leptin levels in alcoholics, we tested the hypothesis of lowered levels as an effect of acute ethanol intake in healthy volunteers. The subjects comprised (1) 17 healthy male participants, recruited via newspaper advertisements [age 29?3.75 years, body mass index (BMI) 24.3?3.5, leptin at baseline 3.3?3.1ng/ml]; (2) for comparison, leptin levels of 16 male alcoholic patients at day 1 of withdrawal were used. They were characterized as follows: (mean, median, standard deviation and range) age in years (41.1, 40.5, 10.2, 24, 57), BMI (23.3, 21.7, 5.4, 16.6, 37.5), 1032g of ethanol (median) consumed within the last 7 days, leptin levels 2.3mg/ml. A placebo-controlled double-blind trial was performed. Leptin levels of blood samples were taken at baseline (t1), before ethanol intake (t2), when blood alcohol had reached its maximum (t3) and the morning after (t4). The oral dose of ethanol administered was 0.6g/kg ethanol. (1) Volunteers: (a) the ethanol and placebo group exhibited leptin levels corresponding closely with levels measured at baseline (t1) (rs=0.85, p 〈0.0001) and follow-up (t4) (rs=0.768, p〈0.0001). (b) Leptin levels for the placebo and the alcohol-consuming (verum) group did not differ significantly at baseline, after ethanol intake or on the morning after [Mann-Whitney U-test (p=0.669, p=1.0 and p=0.887, respectively)]. (2) Leptin levels in relation to BMI did not significantly differ at any measurement time in either group. (3) Leptin levels/BMI of the healthy volunteers at t1 and t4 were not significantly different from those of 16 alcoholics. The data do not support the hypothesis of a significant effect of acute moderate alcohol intake on leptin levels in healthy volunteers.
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  • 21
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In Iran, opium is smoked for pleasure or as a medication by some people. It is a complex mixture of 40 different alkaloids, including morphine and codeine along with many impurities. Although it is well established that opioids or tobacco affect many physiological functions in humans, to our knowledge there has been no specific study looking at these effects in opium smokers. To assess that, we investigated the circulating levels of prolactin, TSH, LH, FSH and testosterone in male opium smokers who also smoke cigarettes (n =23, aged 28.4?4.1 years), and comparing this with the corresponding values for nicotine abusers (n =12, 15–25 cigarettes/day) or a healthy control group (n =20) of the same age. Our results showed that 86.96% of the opium-dependent and 41.67 % of the nicotine-dependent group displayed high prolactin values (p)
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  • 22
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: A hangover is characterized by the unpleasant physical and mental symptoms that occur between 8 and 16 hours after drinking alcohol. After inducing experimental hangover in normal individuals, we measured the methanol concentration prior to and after alcohol consumption and we assessed the association between the hangover condition and the blood methanol level. A total of 18 normal adult males participated in this study. They did not have any previous histories of psychiatric or medical disorders. The blood ethanol concentration prior to the alcohol intake (2.26?2.08) was not significantly different from that 13 hours after the alcohol consumption (3.12?2.38). However, the difference of methanol concentration between the day of experiment (prior to the alcohol intake) and the next day (13 hours after the alcohol intake) was significant (2.62?1.33/l vs. 3.88?2.10/l, respectively). A significant positive correlation was observed between the changes of blood methanol concentration and hangover subjective scale score increment when covarying for the changes of blood ethanol level (r =0.498, p
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  • 23
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    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: As part of a synthesis of evidence regarding the abuse and addiction liability of dextromethorphan (DM), an over-the-counter cough medicine available in over 140 preparations, an uncommonly published case of dextromethorphan dependence (addiction) is described, with specific, rarely published complications. The individual was interviewed and several medical databases were also reviewed (Medline, 1966–present; PubMed) for all content relating to the Keywords: dextromethorphan, abuse, dependence, cough medicine, addiction, withdrawal, psychosis. The patient evidenced history suggesting substance dependence, substance-induced psychosis and substance withdrawal in relation to DM. A literature review revealed that DM has specific serotonergic and sigma-1 opioidergic properties. Dextrorphan (DOR), the active metabolite of DM, has similar properties; however, DOR is a weaker sigma opioid receptor agonist, and a stronger NMDA receptor antagonist. DM and DOR display specific biological features of addiction, and are capable of inducing specific psychiatric sequelae. A specific, reproducible toxidrome with significant psychiatric effects occurred, when DM was abused at greater than indicated doses, with more profound and potentially life-threatening effects at even higher doses. DM withdrawal appears evident. DM's active metabolite, DOR, has pharmacodynamic properties and intoxication effects similar to dissociatives, and may be more responsible for the dissociative effect that this DM abuser sought. However, it is this same metabolite that may be fraught with the potentially life-threatening psychoses and dissociative-induced accidents, as well as addiction. While DM has been hypothesized as the most commonly abused dissociative, health-care providers seem largely unaware of its toxidrome and addiction liability.
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  • 24
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Cyclooxygenase (COX) is reported to play a significant role in neurodegeneration. Recent studies have shown that chronic ethanol administration up-regulates cyclooxygenase expression. In the present study we examined the effect of nimesulide (a preferential COX-2 inhibitor), rofecoxib (a highly selective COX-2 inhibitor) or naproxen (a non-selective COX-inhibitor displaying high affinity towards the COX-1 isoenzyme) on alcohol-induced withdrawal symptoms. Mice were made physically dependent on alcohol by the chronic administration of ethanol (2g/kg of 10% v/v), intragastrically, twice on day 1 and then once-daily on successive days for a total of 7 days. Nimesulide [2.5mg/kg, intraperitoneally (i.p.)], rofecoxib (2mg/kg, i.p.) or naproxen (7mg/kg, i.p.) were administered daily for 7 days before administering alcohol intragastrically. After 24 hours of the last alcohol administration, the treatments were reversed and the mice were tested for withdrawal, so that the animals that had received COX-inhibitors followed 30 minutes later by ethanol on days 1–7 were challenged with saline. Similarly, the animals which received saline followed 30 minutes later by ethanol received only saline. Behavioural analysis revealed hyperlocomotor activity, increased anxious response and increased hyperalgesia in mice. Also, alcohol withdrawal decreased the threshold for Pentylenetetrazole-(PTZ)-induced convulsions. Pretreatment with COX-inhibitors rofecoxib (2mg/kg, i.p.) or nimesulide (2.5mg/kg, i.p.) displayed significant protection against ethanol-induced withdrawal symptoms, while naproxen (7mg/kg, i.p.) was not effective in reversing alcohol-induced withdrawal symptoms. The results of the present study suggest strongly the possible role of cyclooxygenases, particularly COX-2 inhibitors, on ethanol-induced withdrawal symptoms and the potential use of COX-2 inhibitors in their prevention and treatment.
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  • 25
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    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The habit of chewing fresh leaves and twigs of khat (Catha edulis) for their stimulating amphetamine-like effects is highly prevalent in East Africa and southwest on the Arabic peninsula. There is an extensive literature on khat providing information about its history, botany, production, geographical distribution, chemistry and pharmacology, and exploring the social, economic, medical, psychological and oral aspects related to its use. Some of this literature dates as early as the 11th century; however, most of it appeared after the first scientific description of khat by Peter Forskal in 1775. This review provides a panorama of khat and the various aspects of its use. A non-technical description of the plant chemistry and pharmacology is included. The medical, psychological and oral aspects are emphasized, and the current knowledge about the microbiological effects of khat is also presented.
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  • 26
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Chronic exposure to heroin is associated with structural changes in dopaminergic (DA) neurones. The present study examined the effects of a new herbal medicine, U'finer TM capsule, on the brain corpus striatum and DA systems, comparing pre- and post- treatment in 36 heroin-dependent patients. Neuroimaging studies were performed by using single photon emission computed tomography (SPECT) with 99m Tc-TRODAT-1 as radiotracer. The results show that U'finer TM significantly repaired the damaged bilateral corpus striatum, restoring it to a ‘panda eye? shape, analogous in size and shape to that of the healthy volunteers. DA transporter (DAT) function in the bilateral corpus striatum was restored to a normal state after recovery from neurotoxic insult. These findings suggest that U'finer TM is a reliable herbal medicine in the treatment of heroin dependency
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  • 27
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: This is the first trial to compare the relationship of opioid plasma concentrations in methadone-versus buprenorphine-maintained subjects. Sixty subjects (19 females and 41 males) seeking treatment who met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for opioid dependence were recruited and treated at the Drug Addiction Outpatient Clinic at the University of Vienna. Of these, 44 (11 female and 33 male) were included in the analyses of plasma concentrations. Subjects received either daily sublingual buprenorphine (2mg or 8mg tablets; maximum daily dose: 8mg) or oral methadone (racemic R-/S-methadone) and were maintained on a stable dose after an induction period of 2 weeks. Mean dose and mean plasma concentrations were correlated on an individual and collective basis. Correlation was 0.51 for buprenorphine, whereas the score for methadone was 0.69. Intra-individual variation was much higher for buprenorphine (p 〈 0.0001), while the concentration-to-dose ratio was very small. Based on the differences of the pharmacokinetics of blood plasma of the two agents, we tried to explain the differences in the acceptance of treatment, which was significantly lower in the buprenorphine-maintained group. No such differences could be evaluated between completers and dropouts in buprenorphine-maintained subjects, neither concerning withdrawal scores nor dose, plasma concentration, concentration-to-dose ratios or intra-individual variation.
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  • 28
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    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Bupropion exhibits reasonable efficacy as a smoking cessation aid, yet its precise mechanisms of action remain unclear. This review evaluates the mechanism of action of bupropion by considering the clinical evidence in combination with results from pre-clinical experiments in vivo and in vitro. Bupropion is a weak inhibitor of dopamine and noradrenaline reuptake, and has also been shown to antagonise nicotinic acetylcholine receptor function. It is extensively metabolized in humans, its major metabolites reaching levels higher than those of bupropion itself. These metabolites share many of the pharmacological properties of bupropion, so they may play an important role in its clinical activity, yet they have been neglected in investigations into bupropion action. This review led to several conclusions: (1) the principal mode of bupropion action is upon the withdrawal symptoms following smoking cessation; (2) during withdrawal, bupropion may attenuate symptoms by mimicking nicotinic effects on dopamine and noradrenaline; (3) its ability to antagonize nicotinic receptors may prevent relapse by attenuating the reinforcing properties of nicotine, but probably cannot acutely reduce smoking; and (4) further exploration of bupropion metabolites and its role in withdrawal and relapse, within more appropriate animal models, could be crucial in the determination of the precise mechanisms by which bupropion exerts its activity in smoking cessation. Greater elucidation of the exact mechanisms of action of bupropion could lead to the development of new drugs even more beneficial in promoting smoking abstinence.
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  • 29
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Acamprosate (Campral ?) is a drug used clinically for the treatment of alcoholism. In order to examine further the time-course and mechanism of action of acamprosate, the effect of acute and repeated acamprosate administration was examined on (i) operant ethanol self-administration and (ii) voluntary home cage ethanol consumption by alcohol-preferring Fawn-Hooded, iP and Alko Alcohol (AA) rats. Acutely, acamprosate was shown to cause a significant decrease in operant ethanol self-administration by Fawn-Hooded and alcohol-preferring iP rats in part by decreasing the motivational relevance of a specific ethanol cue; however, repeated injection of acamprosate led to tolerance to this effect. Voluntary alcohol consumption in the home cage in Fawn-Hooded and AA rats was also reduced by an acute acamprosate injection; however, again tolerance developed to repeated injections. In a separate experiment, the effect of acamprosate on markers of the dopaminergic system was examined. Interestingly, acute acamprosate was also shown to cause increased dopamine transporter density and decreased dopamine D2-like receptor density within the nucleus accumbens but not in the caudate-putamen, suggesting a link between the decreased motivational salience of the ethanol cue and altered dopaminergic signalling within the nucleus accumbens. With repeated injections of acamprosate, markers of the dopaminergic system returned to steady state levels with a similar temporal profile to the development of tolerance in the behavioural studies. Along with previous studies, our findings indicate that acamprosate modulates the mesolimbic dopaminergic system and may thereby decrease ethanol reinforcement processes; however, these effects undergo tolerance in alcohol-preferring rats and may in part explain the fact why some subjects are non-responders to chronic acamprosate treatment.
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  • 30
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Repeated exposure to addictive drugs results in long-lasting neuroadaptations in the brain, especially in the mesocorticolimbic system. Within this system, the nucleus accumbens (NAc) plays a major integrative role. As such, the NAc has been shown to be a target of short- and long-lasting drug-induced neuroadaptations at the levels of neurotransmission and cellular morphology. The long-lasting neuroadaptations might depend critically on alterations in gene expression. Recently, we obtained a set of transcripts by means of subtractive hybridization, of which the expression was decreased in the rat NAc shell after long-term extinction of intravenous heroin self-administration. Interestingly, the majority of these transcripts were also down-regulated upon long-term extinction of cocaine self-administration. Using the yoked-control operant paradigm, it was shown that non-contingent administration of these drugs resulted in a totally different gene expression profile. However, in the rat NAc core, both self-administration and non-contingent heroin administration induced a qualitatively similar expression profile. Hence, cognitive processes associated with drug self-administration seem to direct the long-term genomic responses in the NAc shell, whereas the NAc core might primarily mediate the persistent pharmacological effects of addictive drugs (including Pavlovian conditioning).
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  • 31
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    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Chronic cocaine abuse induces long-term neurochemical, structural and behavioural changes thought to result from altered gene expression within the nucleus accumbens and other brain regions playing a critical role in addiction. Recent methodological advances now allow the profiling of gene expression in human postmortem brain. In this article, we review studies in which we have used Affymetrix oligonucleotide microarrays to identify transcripts that are differentially expressed in the nucleus accumbens of cocaine abusers in comparison to well-matched control subjects. Of the approximately 39 000 gene transcripts interrogated, the expression of only a fraction of 1% is significantly modified in cocaine abusers. Found within this list are equivalent incidences of increased and decreased transcript abundance, including known gene transcripts clustered into several functional categories. A striking exception is a group of myelin-related genes, consisting of multiple transcripts representing myelin basic protein (MBP), proteolipid protein (PLP) and myelin-associated oligodendrocyte basic protein (MOBP), which as a group are substantially decreased in cocaine abusers compared to controls. These data, suggesting a possible dysregulation of myelin in cocaine abusers, are discussed in the context of myelin-related changes in other human brain disorders. Finally, the effects of cocaine abuse on the profile of gene expression in some other brain regions critical for addiction (the prefrontal cortex and ventral midbrain) are briefly reviewed.
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  • 32
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    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The use of expression profiling with microarrays offers great potential for studying the mechanisms of action of drugs of abuse. Studies with the intact nervous system seem likely to be most relevant to understanding the mechanisms of drug abuse-related behaviours. However, the use of expression profiling with in vitro culture models offers significant advantages for identifying details of cellular signalling actions and toxicity for drugs of abuse. This study discusses general issues of the use of microarrays and cell culture models for studies on drugs of abuse. Specific results from existing studies are also discussed, providing clear examples of relevance for in vitro studies on ethanol, nicotine, opiates, cannabinoids and hallucinogens such as LSD. In addition to providing details on signalling mechanisms relevant to the neurobiology of drugs of abuse, microarray studies on a variety of cell culture systems have also provided important information on mechanisms of cellular/organ toxicity with drugs of abuse. Efforts to integrate genomic studies on drugs of abuse with both in vivo and in vitro models offer the potential for novel mechanistic rigor and physiological relevance.
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  • 33
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    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
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  • 34
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Alcoholism is a complex disease exhibiting a multifactorial mode of transmission. To simplify the genetic and phenotypic complexity of the alcoholic phenotype, alcohol-preferring (P) and -non-preferring (NP) rats were developed on the basis of alcohol preference and consumption as an animal model of alcoholism. Total gene expression analysis (TOGA) and quantitative trait loci (QTL) analysis were applied to selectively bred, inbred P and NP rats as complementary studies to identify genetic factors that contribute to alcohol preference and consumption. TOGA analysis was utilized to screen for differential expression in several brain regions involved in the mesocorticolimbic dopamine (DA) system. Genes exhibiting differences in expression were then screened for an association to the alcohol preference phenotype, the quantitative trait of a previously identified QTL. By evaluating differences in gene expression for linkage to a quantitative trait, this combined approach was implemented to identify α-synuclein, a candidate gene for alcohol preference.
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  • 35
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    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The genetic and environmental contributions to differences in response to ethanol have been examined widely using inbred strains, selected lines and genetically engineered (transgenic and ‘knock-out’) animals. In addition, recombinant inbred strains have been used to identify QTLs (chromosomal regions) associated with particular responses to ethanol. If the polymorphism that underlies such a QTL is localized within the regulatory region of a gene, it could alter the level or stability of the gene product (transcript). This possibility can be addressed by measuring mRNA levels in brains (or other tissue) of inbred or selected lines of animals using DNA microarray technology. In this paper, we review microarray studies conducted in animals that differ in their responses to ethanol. The results of these studies point out the critical nature of the experimental design, statistical analyses and ‘filtering’ procedures for producing interpretable data and identifying candidate genes. In particular, the determination of differentially expressed genes between selected lines of animals, and the localization of the differentially expressed genes within QTLs for the selected phenotype, dramatically increases the probability of identifying genes that contribute to that phenotype through differential expression. Microarray analysis can also be used to assess changes in gene expression that accompany transgene introduction and/or gene ‘knock-out’, which may modulate the influence of the targeted gene on behaviour.
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  • 36
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Alterations in the expression of multiple genes in many brain regions are likely to contribute to psychostimulant-induced behaviours. Microarray technology provides a powerful tool for the simultaneous interrogation of gene expression levels of a large number of genes. Several recent experimental studies, reviewed here, demonstrate the power, limitations and progress of microarray technology in the field of psychostimulant addiction. These studies vary in the paradigms of cocaine or amphetamine administration, drug doses, route and also mode of administration, duration of treatment, animal species, brain regions studied and time of tissue collection after final drug administration. The studies also utilize different microarray platforms and statistical techniques for analysis of differentially expressed genes. These variables influence substantially the results of these studies. It is clear that current microarray techniques cannot detect small changes reliably in gene expression of genes with low expression levels, including functionally significant changes in components of major neurotransmission systems such as glutamate, dopamine, opioid and GABA receptors, especially those that may occur after chronic drug administration or drug withdrawal. However, the microarray studies reviewed here showed cocaine- or amphetamine-induced alterations in the expression of numerous genes involved in the modulation of neuronal growth, cytoskeletal structures, synaptogenesis, signal transduction, apoptosis and cell metabolism. Application of laser capture microdissection and single-cell cDNA amplification may greatly enhance microarray studies of gene expression profiling. The combination of rapidly evolving microarray technology with established methods of neuroscience, molecular biology and genetics, as well as appropriate behavioural models of drug reinforcement, may provide a productive approach for delineating the neurobiological underpinnings of drug responses that lead to addiction.
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  • 37
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    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Microarrays promise dynamic snapshots of cell activity, but microarray results are unfortunately not straightforward to interpret. This article aims to distill the most useful practical results from the vast body of literature availalable on microarray data analysis. Topics covered include: experimental design issues, normalization, quality control, exploratory analysis, and tests for differential expression. Special attention is paid to the peculiarities of low-level analysis of Affymetrix chips, and the multiple testing problem in determining differential expression. The aim of this article is to provide useful answers to the most common practical issues in microarray data analysis. The main topics are pre-processing (normalization), and detecting differential expression. Subsidiary topics include experimental design, and exploratory analysis. Further discussion is found at the author's web page (→ Notes on Microarray Data Analysis).
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  • 38
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Twenty-six in-patients with Diagnostic and Statistical Manual version IV (DSM-IV) criteria for opioid dependence were selected at random to receive either a combination of an 11-day low-dose buprenorphine and a 14-day carbamazepine regimen (n = 14) or a combination of an 11-day methadone and a 14-day carbamazepine regimen (n = 12) in a double-blind, randomized 14-day in-patient detoxification treatment. Patients with buprenorphine and carbamazepine showed a significantly better psychological state after the first and second weeks of treatment. Above all, the buprenorphine-treated patients demonstrated a less marked tiredness, sensitiveness and depressive state as well as a more prominent elevated mood during the detoxification process. Seven non-completers (after 7 days: four of 12 = 33.3%; after 14 days: seven of 12 = 58.3%) were treated with methadone and carbamazepine and five non-completers (after 7 days: two of 14 = 14.3%; after 14 days: five of 14 = 35.7%) received buprenorphine and carbamazepine. The difference in the overall dropout rate after day 14 was not significant. The present study supports the hypothesis that the combination of buprenorphine and carbamazepine leads to a better clinical outcome than does a combination of methadone and carbamazepine in the detoxification of opioid addicts with additional multiple drug abuse. The buprenorphine and carbamazepine-regimen provides a more effective short-term relief of affective disturbances than does methadone and carbamazepine. No severe side effects occurred during the treatment period in both groups.
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  • 39
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Microarray experiments allow researchers to collect an amazing amount of gene expression data that have the potential to provide unique information to help interpretation of the biological functions of the central nervous system. These experiments are, however, technically demanding and present unique difficulties when used in the context of neuroscience research, in particular. Success or failure of microarray experiments are highly dependent on reproducible target preparations. This involves a relatively long chain of preparation steps, such as removal of tissue from experimental animals or from post-mortem human brains, storage, selection, and excision of brain regions. This is followed by RNA extraction, reverse transcription, and labeling of target cDNAs or cRNAs. Additionally, it is emphasized that the quality of microarray data largely relies on the proper handling of animals throughout experiments and the time of the day when experiments are stopped. This article tries to provide hints for some basic rules to be observed in preparation of samples for expression profiling studies.
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  • 40
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    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: A variety of analytical methodologies to investigate gene expression patterns in cells or tissues have been developed. For screening purposes, a large number of target mRNAs have to be interrogated simultaneously. These requirements have been met more or less comprehensively by Differential Display (DD) RT-PCR, Suppression Subtractive Hybridization (SSH), Serial Analysis of Gene Expression (SAGE), and DNA chips. The ultimate goal to cover any gene transcript potentially expressed by a given cell is on the way to be achieved by microbead arrays and by Affymetrix gene chips. Once targets of interest are identified, techniques employing low degrees of multiplexing, such as RNAse protection assays or some bead-based techniques (Luminex) eventually provide extremely fast results on the diagnostic level. With the aid of powerful computer programs, expression profiling technologies have opened intriguing new insights into the complex world of gene regulation. These new techniques have also been applied in drug abuse research recently and some examples of such approaches are described.
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  • 41
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    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Alcoholism is the outcome of complex interactions between the environment and multiple gene loci, which may encode pre-existing susceptibility, or contribute to the neuroadaptations underlying the process of developing dependence. Because of this, the prospect of simultaneous, genome wide, high-throughput analysis of gene expression allowed by microarray technology has met with great expectations. The hope has been that new insights into pathogenesis of substance disorders will rapidly be gained, leading to identification of novel treatment targets. The usefulness of this approach as a discovery tool in addiction research will be critically reviewed here. In this article, we describe the evolution of our experimental approaches, from first generation Affymetrix expression arrays to present high-density arrays, and from the use of original Affymetrix software to more advanced analysis of the probe signal, and different statistical approaches to creating candidate gene lists. Further, we address some methodological issues critical to the study of brain samples by microarray technology. We also summarize findings from several expression profiling experiments involving different animal models of alcoholism. The accumulation of expression data from different animal models allows mining the database for patterns of overlap. Such second level analysis depends on the generation of uniform and reliable datasets.
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  • 42
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    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
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  • 43
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    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
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  • 44
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    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Microarrays are one of several technologies that allow for measurement the expression of thousands of genes simultaneously. This technological advance provides a challenge for the analysis of these data. In this review we discuss these analytical issues from the initial quality control to normalization, differential expression, clustering and finally functional pathway analysis. We focus on Affymetrix data but many of the issues are the same for other array platforms.
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  • 45
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Recent studies have revealed the effectiveness of 2-methyl-6-(phenylethynyl)pyridine (MPEP), a highly selective antagonist of metabotropic glutamate receptors subtype 5 (mGluR5), in conditioned drug reward. In a previous study we showed that MPEP blocks expression of context-conditioned morphine- but not cocaine reward in the rat. The present study now examines the effectiveness of MPEP in the expression of context-conditioned food, MDMA (‘ecstasy?) or amphetamine reward. Therefore, three groups of rats were conditioned either to food, MDMA or amphetamine in the conditioned place preference (CPP) paradigm. After conditioning, CPP expression and locomotion were determined simultaneously in the presence and absence of the respective reward (i.e. food or drug), or after application of 50?mg/kg MPEP (the dose that was most effective in reducing morphine CPP expression in our previous study). As a result, MPEP reduced locomotion in all groups. Furthermore, only expression of amphetamine CPP was inhibited by MPEP, while expression of food and MDMA CPP was not affected, suggesting that the MPEP-induced inhibition of amphetamine CPP expression was not causally linked to the reduction of locomotion. Overall, we conclude that MPEP reduces expression of context-conditioned amphetamine but not MDMA or food reward.
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  • 46
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The aim of this study was to investigate the effectiveness of naltrexone in Taiwanese Han males with alcohol dependence. In conjunction with limited supportive psychotherapy, 40 alcoholic patients, who met Diagnostic and Statistical Manual version III revised (DSM-III-R) criteria for alcohol dependence, were assigned to a randomized double-blind, placebo-controlled trial of naltrexone hydrochloride (50?mg/day) for 14 weeks following alcohol detoxification. Among recruited patients, 45% (n = 9/20) of the naltrexone-treated subjects and 35% (n = 7/20) of the placebo-treated subjects dropped out (p = 0.374). The relapse rates between the two groups were not significant (p = 0.671). Subjects taking naltrexone reported less alcohol craving compared with placebo-treated subjects. In support of previous reports, the present results suggest that naltrexone may be safe and effective in craving reduction in alcohol-dependent subjects.
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  • 47
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In a single-blinded and randomized pilot study efficacy and tolerability of oxcarbazepine versus carbamazepine were investigated in 29 patients during therapy of alcohol withdrawal. No initial differences were found regarding sociodemographic data and alcohol-related parameters, indicating successful randomization. The oxcarbazepine group showed a significant decrease of withdrawal symptoms and reported significantly less ‘craving for alcohol? compared to the carbamazepine group. Subjectively experienced side effects, normalization of vegetative parameters and improvement in the cognitive processing speed did not reveal differences for both groups. Therefore, oxcarbazepine might be an interesting alternative to carbamazepine, and having almost no addictive potential, no clinically relevant interaction with alcohol and no prominent sedatory effect, possibly also to other drugs such as benzodiazepines or clomethiazole, in the treatment of alcohol withdrawal syndrome.
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  • 48
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Polymorphism of a variable number of tandem repeats (VNTR) in the 3′ untranslated region of exon 15 of the SLC6A3 gene, coding for the dopamine transporter (DAT), was analysed to test whether length variation contributes to differences in the individual susceptibility to aggressive – criminal behaviour and liability to heroin dependence. The repeat number of the DAT polymorphism was assessed in 125 healthy subjects and 104 heroin-dependent subjects (including 52 addicted individuals with violent behaviour and criminal records). There was no significant difference in the frequencies of genotypes and alleles between heroin-dependent subjects and control subjects. On the contrary, there was a significant difference between offenders and non-offenders, p  = 0.004 and p  = 0.002, respectively, among heroin-dependent subjects. No association was found between DAT polymorphism and history of suicide. Buss – Durkee Hostility Inventory (BDHI) mean total scores were significantly higher in heroin addicts than in controls (p  〈 0.001) and in antisocial – violent heroin addicts in comparison with addicted individuals without antisocial behaviour (p  〈 0.005). The regression analysis of BDHI subscales, performed to provide an estimate of the magnitude of any potential effect on the risk of aggressiveness associated with the variants in DAT VNTR, showed that the presence of the 9 – 9 genotype significantly increases the risk of irritability and direct aggressiveness more than six and 10 times with respect to the 9 – 10 genotype. Our findings suggest that the 9-repeat allele of the DAT polymorphism confers increased susceptibility to antisocial – violent behaviour and aggressiveness, rather than drug dependence per se in heroin-dependent males.
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  • 49
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: A serotonergic dysfunction was suggested to be involved into the biological susceptibility of suicidal behaviour. Tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis, is a significant regulating factor in the serotonergic system. Recently the A-6526G, and G-5806T and A-779C polymorphisms of the TPH 1 gene were identified and suggested to be associated with suicidal behaviour, but study results are conflicting. We examined a possible association of the A-6526G, and G-5806T and A-779C polymorphisms with suicide attempts in a sample of 80 alcohol-dependent individuals with a history of at least one suicide attempt. This group was analysed in comparison with 241 alcohol-dependent subjects without such a history. No significant relationship between haplotype and genotype distribution and allele frequencies of these polymorphisms with suicide attempts were detected. Furthermore, no association with number of suicide attempts and TPH haplotypes were found. Our data do not support the hypothesis of A-6526G, G-5806T or A-779C polymorphisms to be associated with suicide attempts in alcohol-dependent individuals.
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  • 50
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Narp (neuronal activity-regulated pentraxin) is a secreted immediate early gene product functioning as a cluster factor for the AMPA receptor subtype of glutamate receptors. This study was designed to examine the effects of acute administration of methamphetamine (MAP) on the Narp gene in rat brain using reverse transcription – polymerase chain reaction (RT-PCR). Acute administration of MAP [4.6?mg/kg, intraperitoneally (i.p.)] increased Narp mRNA in the prefrontal cortex, whereas the same treatment with MAP decreased Narp mRNA in the hippocampus. Therefore, Narp gene could be involved in the MAP-induced effects.
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  • 51
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The serotonin transporter (5-HTT) regulates serotonin transmission and modulates behavioral effects of drug of abuse. A polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) yielding a short (S) and long (L) allele has been associated with severity of substance abuse. The aims of the study were to investigate whether 5-HTTLPR genotypes differed in their response to treatment in cocaine- and alcohol-abusing patients. Polymerase chain reaction-based genotyping of a 44 base pair insertion/deletion polymorphism was performed in 141 African American cocaine-dependent patients with concurrent alcohol use who were entering a 12-week behaviorally oriented outpatient treatment program. In treatment, end of treatment and 6-month follow-up outcome measures included changes in Addiction Severity Index (ASI) scores, urine drug screens, days in treatment, individual/group sessions, dropout and completion rates. As expected, there was a reduction in substance abuse by the end of treatment and follow-up (F = 5.15, p = 0.000). However, there were no differences in the reduction in cocaine use across the LL, LS and SS genotypes. Interestingly, individuals with the S allele showed greater severity of alcohol use at admission (F = 4.84, p = 0.03), and the SS genotype showed less improvement in alcohol measures than the LL at follow-up (F = 3.68, p = 0.03), after controlling for baseline variables. While we found no association of the 5-HTTLPR variants with severity of cocaine abuse or any cocaine-related outcome measures, the data suggested that the 5-HTTLPR polymorphism may distinguish responders from non-responders to behavioral treatment in terms of alcohol use. Further investigations are required to determine the role of the 5-HTTLPR polymorphism in influencing treatment – outcome among substance abusers.
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  • 52
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Repeated exposure to stress results in augmentation in the locomotor response to psychostimulant drugs. We investigated the locomotor response to a novel environment or cocaine [10 ? mg/kg, intraperitoneally (i.p.)] and basal corticosterone levels in male adolescent rats exposed to chronic restraint or variable stress. Animals in the chronic restraint group were restrained for 1 hour daily. The chronic variable stress protocol consisted of exposure to different stressors twice a day in random order. Chronic restraint and variable stress regimens began simultaneously on postnatal day (P) 25 and were applied for 10 days. During this period the control group was left undisturbed except for cleaning the cages. Three days after the last exposure to stress, cocaine- and novelty-induced locomotion were recorded in an activity cage. Plasma corticosterone levels were determined in a subset of stress and control animals. Exposure to both chronic restraint and variable stress increased cocaine-induced locomotion and basal corticosterone plasma levels, while no change was observed in the response to a novel environment. Moreover, rats exposed to variable stress displayed the greatest locomotor response following a challenge dose with cocaine when compared to control and chronic restraint stress groups. This observation indicates that the stress regimen is relevant to the degree of stress-induced sensitization to cocaine.
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  • 53
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The ABCB1 gene transporter P-glycoprotein (P-gp) exists in the blood – brain barrier (BBB) and placenta and limits many drugs passing through the BBB and placenta. Several recent studies have raised confounding results regarding the roles of P-gp in nicotine disposition. To ascertain this question, we examined the effects of nicotine and its major oxidative metabolite, cotinine, on ATPase activity using P-gp containing membranes, in which nicotine and cotinine-stimulated inorganic P i was used as a marker of the binding affinity of nicotine and cotinine to P-gp. At concentrations ranging from 5 to 1000 ?μm, both nicotine and cotinine produced modest stimulative effects on ATPase activity in the P-gp containing membrane. The Clint values of nicotine and cotinine were 0.01 and 0.007 minute  − 1  × 10  − 3, respectively. The positive control, verapamil, at concentrations ranging from 1 to 100?μ m, created apparent stimulative effects on ATPase activity, with a Clint value of 1.7 minute  − 1  × 10  − 3, consistent with previously reported results. The results of the current study suggest that nicotine and cotinine were not actively transported by P-gp out of the cells. The observed carrier-mediated nicotine transport in various cell lines may be mediated by other transporter proteins but not P-gp.
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  • 54
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: S-adenosylmethionine (SAM) is an universal methyl donor for biological systems in transmethylation reactions. Another metabolic pathway involving S-adenosylmethionine is initiated with the release of -CH3 from the molecule and the formation of S-adenosylhomocysteine and then homocysteine and cysteine, a precursor of the main cellular antioxidant glutathione. Chronic ethanol consumption could affect the bioavailability of amino acids such as methionine. Our purpose was to determine the effect of chronic alcohol feeding during gestation or lactation on hepatic S-adenosyl-methionine, S-adenosylhomocysteine, DNA methylation and homocysteine serum concentration at the end of the lactation period (21-day-old offspring). Wistar dam rats were fed with alcohol during periconceptional, gestation and lactation periods (alcohol-fed rats). This study was conducted with three groups of offspring with different periods of alcohol exposure: control offspring (C), no treatment; and gestation (G) and lactation (L) offspring, exposed to alcohol only during gestation or lactation, respectively. To obtain these last two groups of offspring, on parturition day control newborn rats were cross-fostered to alcohol-fed dams (L) and alcohol new-born rats were cross-fostered to control dams (G). In conclusion, these results indicate that exposure of rats to ethanol during the lactation period affects SAM values more severely than ethanol exposure only during gestation.
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  • 55
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The opioid receptor antagonist naltrexone, which is used in detoxification and rehabilitation programmes in opioid addicts, can precipitate opioid withdrawal symptoms even in patients who have no opioid present. We tested the hypothesis that in order to precipitate withdrawal, opioids need to convert the inactive opioid receptor site via protein kinase C into a constitutively active form on which the antagonist precipitates withdrawal. Acute abstinence symptoms were induced by the potent opioid receptor agonist sufentanil (21?μg/kg), given for 6 days, which was followed by the antagonist naltrexone (20?μg/kg i.v.) in the awake trained canine (n = 10). Abrupt displacement of opioid binding resulted in acute withdrawal symptoms: increase in blood pressure, heart rate, increase in amplitude height of somatosensory evoked potential, reduced tolerance to colon distention and a significant increase in grading of vegetative variables (restlessness, panting, thrashing of the head, whining, yawning, gnawing, salivation and/or rhinorrhoea, mydriasis, stepping of extremities and vomiting). Following a washout period of 14 days, the same animals were given the highly specific protein kinase C inhibitor H7 (250?μg/kg) prior to the same dosages of sufentanil and naltrexone. Such pretreatment was able to either attenuate or completely abolish the acute withdrawal symptoms. The data suggest that for precipitation of withdrawal, intracellular phosphorylation is a prerequisite in order to activate the opioid μ-receptor. In such a setting, naltrexone acts like an ‘inverse agonist? relative to the action of the antagonist on a non-preoccupied receptor site not being exposed previously to a potent opioid agonist.
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  • 56
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Current clinical practice allows patients with low levels of physiological dependence on opioids (equivalent to methadone doses of 30 ? mg/d or less) to be transferred to buprenorphine. This study investigated the response of opioid – dependent patients receiving doses of methadone between 30 – 70 ? mg/d when transferred to buprenorphine at doses between 12 – 16 ? mg/d. Twenty-three patients receiving inpatient opioid detoxification agreed to take part in a trial of facilitated transfer to buprenorphine. Following the last morning dose of methadone, buprenorphine was substituted in doses increasing from 4 ? mg to a maximum of 16 ? mg, with adjunctive lofexidine (maximum of 2.4 ? mg/d). All except two patients successfully completed transfer to buprenorphine. To investigate the effect of initial methadone dose, the group was split into intermediate dose (ID; 30 – 49 ? mg/d; n = 10) and high dose (HD; 50 – 70 ? mg/d; n = 11) groups. Average stabilisation dose of buprenorphine for the sample who completed transfer was 14.0 ? mg/d (SD 2.3) and average daily lofexidine dose during transfer was 0.57 ? mg (SD 0.39). The HD group used significantly more lofexidine to complete transfer compared to the ID group. Increased opioid withdrawal symptoms, of mild severity as measured by the Short Opiate Withdrawal Scale (SOWS), were found in the HD group compared with the ID group during the first and last day of buprenorphine stabilisation. However, average SOWS scores for the whole of the period of transfer were not significantly different from those during the period of stabilisation on buprenorphine in either the ID or HD groups. This study suggests that transfer to buprenorphine is relatively uncomplicated from daily methadone doses of 30 – 70mg in an inpatient setting and may be facilitated by use of lofexidine. This procedure may allow a larger proportion of opioid-dependent patients access to buprenorphine treatment.
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  • 57
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Repeated opiate administration alters gene expression in different brain regions of rodents, an effect which may contribute to plastic changes associated with addictive behaviour. There is increasing evidence that multiple transcription factors are induced in morphine tolerance, sensitization and during morphine withdrawal. Whereas morphine treatment does not lead to major alterations in the expression of μ-opioid receptors (MOR), there is transcriptional regulation of proteins involved in MOR trafficking such as GRK2 or beta arrestin 2 as well as altered expression of other receptors such as dopamine receptors, NMDA receptors, GABA A receptor and alpha 2A adrenoceptor. Recent gene expression profiling studies reveal additional clusters of morphine-responsive genes: whereas single dose administration has been shown to predominantly reduce expression of genes involved in metabolic function, ascending morphine doses leading to morphine tolerance revealed induction of genes which alter patterns of synaptic connectivity such as arc or ania-3. These genes remained elevated after precipitated withdrawal, which also triggered the expression of several transcriptional activators and repressors. In addition, morphine has been shown to be a strong inducer of heat shock protein 70, a cell protective protein which might counter-regulate opiate-induced neurotoxicity. Temporal expression profiles during a chronic morphine application schedule revealed discrete and fluctuating expression of gene clusters such as transcription factors, G-protein-coupled receptors and neuropeptides. Prolonged abstinence seems to be characterized by up-regulation of several transcription factors and persistent down-regulation of ligand gated ion channels such as glutamatergic and GABA-ergic receptor subunits. These long-term changes in receptor expression suggest a persistent alteration of synaptic signalling after morphine treatment.
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  • 58
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The total concentration of THC has been monitored in cannabis preparations sold in Dutch coffee shops since 1999. This annual monitoring was issued by the Ministry of Health after reports of increased potency. The level of the main psychoactive compound, Δ 9 -tetrahydrocannabinol (THC), is measured in marijuana and hashish. A comparison is made between imported and Dutch preparations, and between seasons. Samples of cannabis preparations from randomly selected coffee shops were analyzed using gas chromatography (GC-FID) for THC, CBD and CBN. In 2004, the average THC level of Dutch home-grown marijuana (Nederwiet) (20.4% THC) was significantly higher than that of imported marijuana (7.0% THC). Hashish derived from Dutch marijuana (Nederhasj) contained 39.3% THC in 2004, compared with 18.2% THC in imported hashish. The average THC percentage of Dutch marijuana, Dutch hashish and imported hashish was significantly higher than in previous years. It nearly doubled over 5 years. During this period, the THC percentage in imported marijuana remained unchanged. A higher price had to be paid for cannabis with higher levels of THC. Whether the increase in THC levels causes increased health risks for users can only be concluded when more data are available on adjusted patterns of use, abuse liability, bioavailability and levels of THC in the brain.
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  • 59
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The importance of craving in alcoholism and the efficacy of treatment has been the subject of various studies. This study focuses on the consumption of different alcoholic beverages and their effect on craving, which has not yet been investigated. Therefore we assessed 197 inpatients using the Obsessive Compulsive Drinking Scale (OCDS) on the day of admission and after 1 week, distinguishing between the total score, the obsessive and the compulsive subscale. Socio-demographic data and the type of alcoholic beverage were recorded. Analysing data, the amount of beer consumption showed a significant influence on craving in male but not in female patients. These results were significant for the total score and both subscales of the OCDS (OCDS total score; day 0: Spearman's rho = 0.31; p = 0.001; logistic regression, dependent variable dichotomized OCDS total score day 0: OR = 1.18; 95% CI = 1.04 – 1.34; p = 0.011). On the other hand we, did not find any significant results for the amount of other beverages such as wine and spirits. Receiver operating curves analysis showed that beer consumption significantly predicts craving [area under the curve (AUC) = 0.66; p = 0.002]. We conclude that higher beer consumption is associated with higher withdrawal craving, at least in male patients. In addition, it is an important predictor for both obsessive and compulsive craving. Further studies are needed to clarify the pathophysiological basis of this finding.
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  • 60
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Several studies indicate long-term cognitive impairment of MDMA (ecstasy) users. In the present study we attempted to establish whether electrophysiological correlates of low-level cognitive processes present a long-term alteration, dependent on the level of use of ecstasy. We addressed this issue by investigating amplitude and latency of VEPs related to a very simple discrimination task involving sustained attention (arousal). Eight heavy-MDMA users, eight moderate-MDMA users and 18 drug-free control subjects were asked to discriminate whether the digit at the centre of the screen was 1 or 2. None of the subjects (except one) had used MDMA in the 6 months previous testing. We measured psychophysical performance and EEG, recorded in Oz and Fz during task execution. The heavy-MDMA users made significantly more errors than the other two groups (p 〈 .05). Moreover, they presented reduced amplitude but not latency of VEPs in both Oz and Fz. The effect in Oz is present in P200 (for heavy users only, p 〈 .05) and in P300 components (for both MDMA groups; heavy users: p 〈 .001, moderate users: p 〈 .0.5). In Fz, the amplitude effect is present in N250 (for heavy users only, p 〈 .05) and in P300 components (for both MDMA groups; heavy users: p 〈 .05, moderate users: p 〈 .05). The three groups do not differ in early components, reflecting low-level processing. These results provide evidence of long-term electrophysiological abnormality displayed by ecstasy users and agree with the suggestion that even typical recreational doses of ecstasy are sufficient to cause long-term altered cortical activity in humans.
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  • 61
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
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  • 62
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Several lines of evidence suggest that genetic factors contribute to the vulnerability of drug abuse such as methamphetamine (MAP), and that dopamine-quinones produced by administration of MAP may be involved in the mechanism of MAP-related symptoms. The detoxification of quinones is catalyzed by a family of proteins designated as quinone oxidoreductases (NQOs). We analysed the polymorphisms of NQO1 and NQO2 genes to elucidate the association with genetic vulnerability to MAP abuse in Japan. The genotype and allele frequencies for the polymorphism (Pro187Ser) of the NQO1 gene did not differ between each subgroup of patients and controls. In contrast, the genotype frequency for the insertion/deletion (I/D) polymorphism in the promoter region of the NQO2 gene was a significant (p = 0.038) difference between patients with prolonged-type MAP psychosis and controls. This study suggests that the NQO2 gene polymorphism contributes to the aetiology of MAP-related psychosis in Japanese.
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  • 63
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Book reviewed in this article:Book reviews in this column will primarily be of titles focusing completely, or in part, on biological aspects of addiction. However, signi.cant titles of general relevance to the addictions .eld will also be included, even if they are not “biological”, as will titles of general methodological and clinical relevance, even if they are not on “addictions”. Similar considerations will apply to other media (software, audio tapes and CDs, videos, etc.). However, specific “addictions” software applications seem to be relatively uncommon and, as these items are rarely reviewed elsewhere, we will endeavour to include reviews of some of the older programmes that are still useful, as well as new titles that appear. I would appreciate suggestions of any items suitable for reviews, but especially software and other media of specific relevance to the addictions. Please contact: Dr David Ball, National Addiction Centre, 4 Windsor Walk, London SE5 8 AF, UK. Email: media@addictionbiology.com Medical Statistics from Scratch DAVID BOWERS Neurobiology of Addictions: Implications for Clinical Practice RICHARD T. SPENCE, DIANA M. DINITTO, SHULAMITH LALA ASHENBERG STRAUSSNER (Eds) Drug Users in Society J NEALE Treatment Matching in Alcoholism T.F. BABOR & F. DEL BOCA (Eds)
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  • 64
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Opioid withdrawal, stress or cues associated with opioid consumption can induce opioid craving. If opioids are not available, opioid-dependent patients usually search for alternative drugs. Because several non-opioid drugs stimulate the endogenous opioidergic system, this concept may explain their frequent use by opioid-dependent patients. We hypothesized that non-opioid drugs alleviate opioid withdrawal symptoms and are therefore consumed by opioid addicts. We asked 89 opioid-dependent patients participating in an out-patient opioid maintenance program to estimate the potential of several non-opioid drugs in being able to alleviate opioid withdrawal. We applied a five-point Lickert scale (1 = very good reduction of opioid withdrawal; 5 = no reduction of opioid withdrawal). Patients could also indicate a worsening of opioid withdrawal. Values (mean ? SD) were: for benzodiazepines, 3.2 ? 1.1; tricyclic antidepressants, 3.6 ? 1.1; cannabis, 3.6 ? 1.0; alcohol, 4.1 ? 1.1; cocaine, 4.2 ? 1.1; amphetamine, 4.4 ? 0.9; nicotine, 4.7 ? 0.7; and caffeine, 4.9 ? 0.5. A worsening of opioid withdrawal was reported by 62% of the patients for cocaine, 62% for amphetamine, 50% for caffeine, 37.5% for cannabis, 27% for nicotine, 26% for alcohol, 8% for tricyclic antidepressants and 3% for benzodiazepines. Our study shows a low efficacy of non-opioid drugs in alleviating opioid withdrawal symptoms. The data basis of this study was good and the sample was suitable to be asked for estimations of drug-drug interactions. Of the patients, 26 – 62% even reported a worsening of opioid withdrawal for cannabis, alcohol, cocaine and amphetamine. Only benzodiazepines and tricyclic antidepressants were reported to have a moderate positive effect on opioid withdrawal.
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  • 65
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
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  • 66
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Addiction biology 10 (2005), S. 0 
    ISSN: 1369-1600
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
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  • 67
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    British journal of dermatology 153 (2005), S. 0 
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The nematode Caenorhabditis elegans has proven a robust genetic model for studies of aging and the roles of stress. In this review we focus on the genetics of select long-lived and short-lived mutants of C. elegans that have proven useful in revealing the relationships that exist between oxidative stress and life span. The former are known to be controlled by an insulin/insulin-like signaling pathway, while the latter are affected by mitochondrial functions.
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  • 68
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background  Chronic ultraviolet (UV) radiation from sunlight induces wrinkle formation. Retinoic acid (RA) can markedly improve wrinkles, although RA does have some side-effects, such as skin irritation. As the efficacy and cytotoxicity of RA has been traced to its free carboxylic acid, we synthesized a new molecule, N-retinoyl-D-glucosamine (GRA), in which a glucosamine has been attached to the polar end group of all-trans retinoic acid.Objectives  To analyse the effect of topical GRA in wrinkle repair and anti-irritation in photoaged mice compared with topical RA, as well as to determine retinoic acid receptor (RAR) and retinoid X receptor (RXR) transactivation activity in vitro.Methods  Hairless mice were irradiated with 60 mJ cm−2 of UVB for 10 weeks, and then topically treated with 0·05% GRA or 0·05% RA for 8 weeks. An in vitro transcriptional assay was performed and the activity of GRA in 293 cells transfected with RAR-α or RXR-α expression plasmid and luciferase reporter plasmid then determined.Results  Topical GRA and RA brought about almost complete disappearance of the wrinkles caused by UVB irradiation. The two ligands promoted both a wide repair zone histologically, and the expression of type 1 collagen in the skin. In contrast, topical GRA treatment did not produce irritation such as erythema or roughness, or alteration of transepidermal water loss values, compared with RA. In the in vitro luciferase assay, GRA resulted in significant dose-dependent RAR transactivation activity in a 100 times higher concentration range than RA. GRA did not mediate RXR transactivation activity at all.Conclusions  Topical GRA appears to be able to repair photoaged skin damage without any of the irritation caused by topical RA, probably via RAR transactivation activity.
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  • 69
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background  The naevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by tumorigenesis such as multiple basal cell carcinomas, odontogenic keratocysts and developmental abnormalities such as calcified dural folds and rib-anomalies. Recently, it has been shown that ultraviolet (UV) B exposure produced more BCCs in ptch knockout mice than wild mice.Objectives  To Investigate the role of UV in development of BCCs in NBCCS, cellular sensitivity to killing by UVB and removal of UVB-induced oxidative DNA damage were examined using fibroblasts derived from patients with NBCCS under physiologically relevant doses of UVB exposure.Patients and methods  Three patients with NBCCS, a 59-year-old male patient, an 18-year-old boy and a 13-year-old boy were examined by photobiological analysis. Cellular sensitivity to killing by UVB and UVC and removal of oxidative DNA damage caused by UVB were tested using fibroblasts derived from these patients. We measured cellular 8-hydroxydeoxyguanosine (8-OHdG) after UVB exposure up to 24 h after UVB exposure using high-performance liquid chromatography.Results  All three cell strains derived from the patients with NBCCS were hypersensitive to killing by UVB (D10: 50–70% of normal) but not by UVC. After UVB exposure, the production of 8-OHdG increased dose dependently up to 3200 J m−2 in both NBCCS cells and normal cells. In normal cells, 8-OHdG after UVB exposure returned to its basal level during 24 h, whereas in NBCCS cells the amount of 8-OHdG after 800 J m−2 of UVB exposure did not return to its basal level even after 24 h. The result indicates the removal of 8-OHdG could be impaired in NBCCS cells. Ability in removal of thymine dimers of NBCCS cells was similar to that of normal cells.Conclusions  Hypersensitivity to UVB can be one of the diagnostic tools of NBCCS for those whose clinical features have not yet completed. Hypersensitivity to cell killing and the impairment of removal of 8-OHdG after UVB exposure may play some role in developing BCCs and other tumours in NBCCS.
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  • 70
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background  The majority of skin changes associated with ageing are caused by photoageing and reflect cumulative sun exposure. Although the actinic damage plays a major role in skin pigmentation, it is also important to examine the effects of chronological cellular ageing on the pigmentation. The chief cellular components of the skin other than melanocytes are keratinocytes and fibroblasts, and the influences of age-related changes in those cells on skin pigmentation have not been elucidated.Objective  To clarify the effects of cellular ageing of keratinocytes and fibroblasts on age-related skin pigmentation.Methods  Using ELISA analysis, we measured the level of melanogenic cytokines secreted by cultured keratinocytes and fibroblasts derived from skin of various chronological ages. We also compared the cytokine secretion by cultured keratinocytes between the second and fifth cultures.Results  There was no correlation between age and hepatocyte growth factor (HGF), stem cell factor (SCF), and basic fibroblast growth factor (bFGF) secretion by fibroblasts. On the other hand, a significant positive correlation existed between age and interleukin ((IL)-1α secretion (R2 = 0·50, P = 0·002), and a relatively weak correlation existed between age and endothelin-1 (ET-1) secretion (R2 = 0·17, P = 0·051, not significant). The IL-1α secretion by keratinocytes was significantly increased in the fifth cultures compared with the second cultures (P 〈 0·005).Conclusions  These findings suggest that IL-1α secretion increases as cells grow older, and the increased secretion of IL-1α by aged keratinocytes may stimulate HGF production in dermal fibroblasts paracrinely and ET-1 production in keratinocytes autocrinely, which stimulates melanocyte proliferation and induces an increase of tyrosinase activity in melanocytes. Because IL-1α is a primary mediator that responds to inflammation and injury, the transcription of genes involved in skin inflammation may be persistently induced in the aged skin. Thus the increased secretion of IL-1α by aged keratinocytes in the aged skin may play a role in the accentuated cutaneous pigmentation and other skin ageing.
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    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    British journal of dermatology 152 (2005), S. 0 
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005