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  • MEK-dependent negative feedback underlies BCR-ABL-mediated oncogene addiction. 24362263

    The clinical experience with BCR-ABL tyrosine kinase inhibitors (TKI) for the treatment of chronic myelogenous leukemia (CML) provides compelling evidence for oncogene addiction. Yet, the molecular basis of oncogene addiction remains elusive. Through unbiased quantitative phosphoproteomic analyses of CML cells transiently exposed to BCR-ABL TKI, we identified persistent downregulation of growth factor receptor (GF-R) signaling pathways. We then established and validated a tissue-relevant isogenic model of BCR-ABL-mediated addiction, and found evidence for myeloid GF-R signaling pathway rewiring that profoundly and persistently dampens physiologic pathway activation. We demonstrate that eventual restoration of ligand-mediated GF-R pathway activation is insufficient to fully rescue cells from a competing apoptotic fate. In contrast to previous work with BRAF(V600E) in melanoma cells, feedback inhibition following BCR-ABL TKI treatment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR-ABL-mediated oncogene addiction is facilitated by persistent high levels of MAP-ERK kinase (MEK)-dependent negative feedback.We found that BCR–ABL can confer addiction in vitro by rewiring myeloid GF-R signaling through establishment of MEK-dependent negative feedback. Our findings predict that deeper, more durable responses to targeted agents across a range of malignancies may be facilitated by maintaining negative feedback concurrently with oncoprotein inhibition.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    05-516
    Produktbezeichnung:
    Anti-Ras Antibody, clone RAS10

  • Quantitative analysis of AMPA receptor subunit composition in addiction-related brain regions. 20946890

    The subunit composition of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) is an important determinant of AMPAR biophysical properties and trafficking. To date, AMPAR subunit composition has been quantitatively evaluated only for the hippocampus, where different experimental approaches have yielded different results. Here, we used quantitative co-immunoprecipitation to characterize GluA1-3 associations in the adult rat nucleus accumbens, dorsal striatum, prefrontal cortex, and hippocampus, and blue native electrophoresis (BNE) to study GluA1-3 assembly state. In all brain regions, co-immunoprecipitation experiments showed that ~90% of GluA1 was associated with GluA2 or GluA3 (most was GluA1A2). All regions contained a small number of GluA1A3 receptors. Homomeric GluA1 receptors may also exist. More than half of the GluA2 (53%-65% depending on the region) was not associated with GluA1. However, this represents an over-estimate of the percent of GluA2 present in GluA2A3 receptors, based on BNE results demonstrating that the majority of GluA2 exists as dimers, rather than functional tetrameric receptors. Relatively more GluA1 was present in tetramers. Together with other findings, our results suggest a dominant role for GluA1A2 receptors in all brain regions examined. They also help explain why different results for hippocampal AMPAR subunit composition were obtained using co-immunoprecipitation, which assesses the total cellular pool of AMPARs including partially assembled AMPARs in intracellular compartments, and electrophysiological approaches, which can selectively assess tetrameric (functional) AMPARs on the cell surface.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    Mehrere
    Produktbezeichnung:
    Mehrere

  • Methadone induces necrotic-like cell death in SH-SY5Y cells by an impairment of mitochondrial ATP synthesis. 20691259

    Methadone is a widely used therapeutic opioid in narcotic addiction and neuropathic pain syndromes. Oncologists regularly use methadone as a long-lasting analgesic. Recently it has also been proposed as a promising agent in leukemia therapy, especially when conventional therapies are not effective. Nevertheless, numerous reports indicate a negative impact on human cognition with chronic exposure to opiates. Thus, clarification of methadone toxicity is required. In SH-SY5Y cells we found that high concentrations of methadone were required to induce cell death. Methadone-induced cell death seems to be related to necrotic processes rather than typical apoptosis. Cell cultures challenged with methadone presented alterations in mitochondrial outer membrane permeability. A mechanism that involves Bax translocation to the mitochondria was observed, accompanied with cytochrome c release. Furthermore, no participation of known protein regulators of apoptosis such as Bcl-X(L) and p53 was observed. Interestingly, methadone-induced cell death took place by a caspases-independent pathway; perhaps due to its ability to induce a drastic depletion in cellular ATP levels. Therefore, we studied the effect of methadone on isolated rat liver mitochondria. We observed that methadone caused mitochondrial uncoupling, coinciding with the ionophoric properties of methadone, but did not cause swelling of the organelles. Overall, the effects observed for cells in the presence of supratherapeutic doses of methadone may result from a "bioenergetic crisis." A decreased level of cellular energy may predispose cells to necrotic-like cell death.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    MAB1622
    Produktbezeichnung:
    Anti-Spectrin alpha chain (nonerythroid) Antibody, clone AA6

  • Dopamine neurons in the ventral tegmental area fire faster in adolescent rats than in adults. 22723669

    Adolescence may be a period of vulnerability to drug addiction. In rats, elevated firing activity of ventral tegmental area (VTA) dopamine neurons predicts enhanced addiction liability. Our aim was to determine if dopamine neurons are more active in adolescents than in adults and to examine mechanisms underlying any age-related difference. VTA dopamine neurons fired faster in adolescents than in adults as measured with in vivo extracellular recordings. Dopamine neuron firing can be divided into nonbursting (single spikes) and bursting activity (clusters of high-frequency spikes). Nonbursting activity was higher in adolescents compared with adults. Frequency of burst events did not differ between ages, but bursts were longer in adolescents than in adults. Elevated dopamine neuron firing in adolescent rats was also observed in cell-attached recordings in ex vivo brain slices. Using whole cell recordings, we found that passive and active membrane properties were similar across ages. Hyperpolarization-activated cation currents and small-conductance calcium-activated potassium channel currents were also comparable across ages. We found no difference in dopamine D2-class autoreceptor function across ages, although the high baseline firing in adolescents resulted in autoreceptor activation being less effective at silencing neurons. Finally, AMPA receptor-mediated spontaneous excitatory postsynaptic currents occurred at lower frequency in adolescents; GABA(A) receptor-mediated spontaneous inhibitory postsynaptic currents occurred at both lower frequency and smaller amplitude in adolescents. In conclusion, VTA dopamine neurons fire faster in adolescence, potentially because GABA tone increases as rats reach adulthood. This elevation of firing rate during adolescence is consistent with it representing a vulnerable period for developing drug addiction.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    AB152
    Produktbezeichnung:
    Anti-Tyrosine Hydroxylase Antibody

  • Region and context-specific intracellular responses associated with cocaine-induced conditioned place preference expression. 25522720

    The development and maintenance of cocaine addiction depend heavily on learned reward-environment associations that can induce drug-seeking behavior and relapse. Understanding the mechanisms underlying these cue-induced conditioned responses is important for relapse prevention. To test whether intracellular responses measured after cocaine conditioned place preference (CPP) expression are context-dependent, we re-exposed cocaine-treated rats (drug-free) to an environment previously paired with cocaine or saline, 24h after the CPP test. After 8 days of cocaine CPP training with one of two cocaine doses (5mg/kg or 20mg/kg, i.p.), CPP was expressed only after conditioning with the higher cocaine dose. In CPP expressing rats, locomotor responses after re-exposure to the cocaine-chamber were greater than in rats re-exposed to the saline-paired chamber. Nucleus Accumbens (NAc) phosphorylated ERK (pERK) levels were increased after re-exposure to the cocaine-paired, but not the saline-paired chamber, regardless of whether or not CPP behavior was expressed. Caudate Putamen (CPu) pERK and FosB protein levels increased after re-exposure to the cocaine chamber only after conditioning with the higher cocaine dose. Conversely, the higher cocaine dose, independent of environment, resulted in increased NAc FosB, ΔFosB and phosphorylated CREB (pCREB) protein levels compared to those conditioned with 5mg/kg cocaine (non-CPP-expressing). Our results suggest that NAc ERK phosphorylation may be involved with retrieving the contextual information of a cocaine-association, without necessarily motivating the expression of CPP behavior. Additionally, we show distinct patterns of intracellular responses in the NAc and CPu indicating a region-specific role for pERK/pCREB/FosB intracellular signaling in the retrieval of cocaine-context associations.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    06-519
    Produktbezeichnung:
    Anti-phospho-CREB (Ser133) Antibody

  • Chronic nicotine pretreatment is sufficient to upregulate α4* nicotinic receptors and increase oral nicotine self-administration in mice. 25038610

    Understanding the underlying causes of nicotine addiction will require a multidisciplinary approach examining the key molecular, cellular and neuronal circuit functional changes that drive escalating levels of nicotine self-administration. In this study, we examined whether mice pretreated with chronic nicotine, at a dosing regimen that results in maximal nicotinic acetylcholine receptor (nAChR) upregulation, would display evidence of nicotine-dependent behaviour during nicotine self-administration.We investigated oral self-administration of nicotine using a two-bottle choice paradigm in which one bottle contained the vehicle (saccharine-sweetened water), while the other contained nicotine (200 μg/ml) in vehicle. Knock-in mice with YFP-tagged α4 nAChR subunits (α4YFP) were implanted with osmotic pumps delivering either nicotine (2 mg/kg/hr) or saline for 10 days. After 10 days of pretreatment, mice were exposed to the nicotine self-administration paradigm, consisting of four days of choice followed by three days of nicotine abstinence repeated for five weeks. Mice pre-exposed to nicotine had upregulated α4YFP nAChR subunits in the hippocampal medial perforant path and on ventral tegmental area GABAergic neurons as compared to chronic saline mice. Compared to control saline-pretreated mice, in a two bottle-choice experiment, nicotine-primed mice ingested a significantly larger daily dose of nicotine and also exhibited post-abstinence binge drinking of nicotine.Chronic forced pre-exposure of nicotine is sufficient to induce elevated oral nicotine intake and supports the postulate that nAChR upregulation may be a key factor influencing nicotine self-administration.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    MAB5406
    Produktbezeichnung:
    Anti-GAD67 Antibody, clone 1G10.2

  • Nucleus accumbens neurons exhibit synaptic scaling that is occluded by repeated dopamine pre-exposure. 19674091

    Synaptic scaling has been proposed as a form of plasticity that may contribute to drug addiction but it has not been previously demonstrated in the nucleus accumbens (NAc), a critical region for addiction. Here we demonstrate bidirectional synaptic scaling in postnatal rat NAc neurons that were co-cultured with prefrontal cortical neurons to restore excitatory input. Prolonged activity blockade (1-3 days) with an AMPA receptor antagonist increased cell surface (synaptic and extrasynaptic) glutamate receptor 1 (GluR1) and GluR2 but not GluR3, as well as GluR1/2 co-localization on the cell surface and total GluR1 and GluR2 protein levels. A prolonged increase in activity (bicuculline, 48 h) produced opposite effects. These results suggest that GluR1/2-containing AMPA receptors undergo synaptic scaling in NAc neurons. GluR1 and GluR2 surface expression was also increased by tetrodotoxin alone or in combination with an N-methyl-d-aspartate receptor or AMPA receptor antagonist but not by the l-type Ca(2+) channel antagonist nifedipine. A cobalt-quenching assay confirmed the immunocytochemical results indicating that synaptic scaling after activity blockade did not involve a change in abundance of GluR2-lacking AMPA receptors. Increased AMPA receptor surface expression after activity blockade required protein synthesis and was occluded by inhibition of the ubiquitin-proteasome system. Repeated dopamine (DA) treatment, which leads to upregulation of surface GluR1 and GluR2, occluded activity blockade-induced synaptic scaling. These latter results indicate an interaction between cellular mechanisms involved in synaptic scaling and adaptive mechanisms triggered by repeated DA receptor stimulation, suggesting that synaptic scaling may not function normally after exposure to DA-releasing drugs such as cocaine.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    MAB397
    Produktbezeichnung:
    Anti-Glutamate Receptor 2 Antibody, extracellular, clone 6C4

  • Organization of GABAergic synaptic circuits in the rat ventral tegmental area. 23056271

    The ventral tegmental area (VTA) is widely implicated in drug addiction and other psychiatric disorders. This brain region is densely populated by dopaminergic (DA) neurons and also contains a sparse population of γ-aminobutyric acid (GABA)ergic cells that regulate the activity of the principal neurons. Therefore, an in-depth knowledge of the organization of VTA GABAergic circuits and of the plasticity induced by drug consumption is essential for understanding the mechanisms by which drugs induce stable changes in brain reward circuits. Using immunohistochemistry, we provide a detailed description of the localization of major GABA(A) and GABA(B) receptor subunits in the rat VTA. We show that DA and GABAergic cells express both GABA(A) and GABA(B) receptors. However VTA neurons differ considerably in the expression of GABA(A) receptor subunits, as the α1 subunit is associated predominantly with non-DA cells, whereas the α3 subunit is present at low levels in both types of VTA neurons. Using an unbiased stereological method, we then demonstrate that α1-positive elements represent only a fraction of non-DA neurons and that the ratio of DA and non-DA cells is quite variable throughout the rostro-caudal extent of the VTA. Interestingly, DA and non-DA cells receive a similar density of perisomatic synapses, whereas axo-dendritic synapses are significantly more abundant in non-DA cells, indicating that local interneurons receive prominent GABAergic inhibition. These findings reveal a differential expression of GABA receptor subtypes in the two major categories of VTA neurons and provide an anatomical basis for interpreting the plasticity of inhibitory circuits induced by drug exposure.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    MAB377
    Produktbezeichnung:
    Anti-NeuN Antibody, clone A60

  • Selective activation of cholinergic interneurons enhances accumbal phasic dopamine release: setting the tone for reward processing. 22840394

    Dopamine plays a critical role in motor control, addiction, and reward-seeking behaviors, and its release dynamics have traditionally been linked to changes in midbrain dopamine neuron activity. Here, we report that selective endogenous cholinergic activation achieved via in vitro optogenetic stimulation of nucleus accumbens, a terminal field of dopaminergic neurons, elicits real-time dopamine release. This mechanism occurs via direct actions on dopamine terminals, does not require changes in neuron firing within the midbrain, and is dependent on glutamatergic receptor activity. More importantly, we demonstrate that in vivo selective activation of cholinergic interneurons is sufficient to elicit dopamine release in the nucleus accumbens. Therefore, the control of accumbal extracellular dopamine levels by endogenous cholinergic activity results from a complex convergence of neurotransmitter/neuromodulator systems that may ultimately synergize to drive motivated behavior.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    AB144P
    Produktbezeichnung:
    Anti-Choline Acetyltransferase Antibody