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Long-lasting tolerance to alcohol following a history of dependence.
No full textTolerance to alcohol effects is one of the defining features of clinical alcohol dependence. Here, we hypothesized that the post-dependent state may include tolerance to sedative-hypnotic alcohol actions. To address this question, we used a recently developed animal model in which repeated cycles of alcohol intoxication and withdrawal trigger long-lasting behavioral plasticity. This animal model shares important features with the clinical condition. Animals were exposed to 7 weeks of intermittent alcohol vapor, allowed to recover for 3 weeks, and tested in protracted abstinence to exclude contributions from acute withdrawal. Post-dependent and control rats were injected with a hypnotic dose of alcohol (3 g/kg), and the loss of righting reflex (LORR) was recorded, blood alcohol levels were monitored, and the elimination rate was calculated. Post-dependent animals showed a decrease in LORR. Alcohol metabolism and elimination kinetics did not differ between groups. In conclusion, a history of alcohol dependence induces long-lasting hypnotic tolerance. This process may play an important role in maintaining the dependent state
Neuroplasticity in brain reward circuitry following a history of ethanol dependence.
No full textMitogen-activated and extracellular regulated kinase (MEK) and extracellular signal-regulated protein kinase (ERK) pathways may underlie ethanol-induced neuroplasticity. Here, we used the MEK inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (UO126) to probe the role of MEK/ERK signaling for the cellular response to an acute ethanol challenge in rats with or without a history of ethanol dependence. Ethanol (1.5 g/kg, i.p.) induced expression of the marker genes c-fos and egr-1 in brain regions associated with both rewarding and stressful ethanol actions. Under non-dependent conditions, ethanol-induced c-fos expression was generally not affected by MEK inhibition, with the exception of the medial amygdala (MeA). In contrast, following a history of dependence, a markedly suppressed c-fos response to acute ethanol was found in the medial pre-frontal/orbitofrontal cortex (OFC), nucleus accumbens shell (AcbSh) and paraventricular nucleus (PVN). The suppressed ethanol response in the OFC and AcbSh, key regions involved in ethanol preference and seeking, was restored by pre-treatment with UO126, demonstrating a recruitment of an ERK/MEK-mediated inhibitory regulation in the post-dependent state. Conversely, in brain areas involved in stress responses (MeA and PVN), an MEK/ERK-mediated cellular activation by acute ethanol was lost following a history of dependence. These data reveal region-specific neuroadaptations encompassing the MEK/ERK pathway in ethanol dependence. Recruitment of MEK/ERK-mediated suppression of the ethanol response in the OFC and AcbSh may reflect devaluation of ethanol as a reinforcer, whereas loss of an MEK/ERK-mediated response in the MeA and PVN may reflect tolerance to its aversive actions. These two neuroadaptations could act in concert to facilitate progression into ethanol dependence
Transcription factor gene expression profiling after acute intermittent nicotine treatment in the rat cerebral cortex
No full textSeveral studies in different in vitro and in vivo models have demonstrated neuroprotective effects of nicotinic receptor agonists and indirect trophic actions of nicotine on brain are suggested from observations describing nicotine as a cognitive enhancer by increasing vigilance and improving learning and memory. While an increasing number of studies have given evidence of neuroprotective and neurotrophic effects of nicotine treatment, the molecular mechanism mediating the neurotrophic effects of nicotine are not fully understood. Previously in an analysis of several neurotrophic factors as possible mediators of nicotine-induced neuroprotection and/or neurotrophic effects we could reveal that an acute intermittent nicotine treatment increases fibroblast growth factor-2 mRNA and protein in several brain regions of rat brain. Even if other studies have demonstrated in different paradigms that nicotine administration modulates expression level of a variety of genes, there is still a lack of indication which candidate genes, involved in neuroprotective responses are modulated by nicotine. In the present work we have used a microarray assay to further find and characterize new genes responsive to acute intermittent nicotine treatment and linked to neuroprotection. Therefore, we used Rat Genome U34A Affymetrix GeneChip arrays containing about 8800 probe sets to characterize transcriptional responses in the rat parietal cortex after acute intermittent nicotine treatment. We focused our attention to expression of transcription factors and several of them were up- or down-regulated by nicotine, among these Nr4a1 (Nurr77), Egr-1 and Egr-2. In situ hybridization was used to corroborate the microarray data and to reveal further spatial and temporal patterns of these nicotine induced genes. Taken together the present results identified several novel candidate genes modified by acute intermittent nicotine exposure and as such potentially involved in neuroprotective-neurotrophic actions
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Validation of neural biomarkers for predicting naltrexone response in patients with alcohol dependence: a longitudinal functional magnetic resonance imaging study
No full textVariation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress
No full textAlcoholism is a chronic relapsing disorder with substantial heritability.
Uncovering gene–environment interactions underlying this
disease process can aid identification of novel treatment targets.
Here, we found a lowered threshold for stress-induced reinstatement of alcohol seeking in Marchigian–Sardinian Preferring (msP) rats genetically selected for high alcohol preference. In situ hybridization for a panel of 20 stress-related genes in 16 brain regions was used to screen for differential gene expression that may underlie this behavioral phenotype. An innate up-regulation of the Crhr1 transcript, encoding the corticotropin-releasing hormone receptor 1 (CRH-R1), was found in several limbic brain areas of msP
rats genetically selected for high alcohol preference, was associated with genetic polymorphism of the Crhr1 promoter, and was accompanied by increased CRH-R1 density. A selective CRH-R1 antagonist (antalarmin, 10–20 mgkg) was devoid of effects on operant alcohol self-administration in unselected Wistar rats but significantly suppressed this behavior in the msP line. Stress induced reinstatement of alcohol seeking was not significantly
affected by antalarmin in Wistar rats but was fully blocked in msP animals. These data demonstrate that Crhr1 genotype and expression interact with environmental stress to reinstate alcohol-seeking behavior
Attenuation of alcohol-cue modulated insula connectivity by naltrexone predicts relapse in alcohol-dependent patients: a longitudinal clinical neuroimaging trial
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