Página 2 dos resultados de 57 itens digitais encontrados em 0.000 segundos

‣ High-Resolution BAC-Based Map of the Central Portion of Mouse Chromosome 5

Crabtree, Jonathan; Wiltshire, Tim; Brunk, Brian; Zhao, Shaying; Schug, Jonathan; Stoeckert, Christian J.; Bucan, Maja
Fonte: Cold Spring Harbor Laboratory Press Publicador: Cold Spring Harbor Laboratory Press
Tipo: Artigo de Revista Científica
Publicado em /10/2001 Português
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The current strategy for sequencing the mouse genome involves the combination of a whole-genome shotgun approach with clone-based sequencing. High-resolution physical maps will provide a foundation for assembling contiguous segments of sequence. We have established a bacterial artificial chromosome (BAC)-based map of a 5-Mb region on mouse Chromosome 5, encompassing three gene families: receptor tyrosine kinases (PdgfraKit-Kdr), nonreceptor protein-tyrosine type kinases (Tec–Txk), and type-A receptors for the neurotransmitter GABA (Gabra2, Gabrb1, Gabrg1, and Gabra4). The construction of a BAC contig was initiated by hybridization screening the C57BL/6J (RPCI-23) BAC library, using known genes and sequence tagged sites (STSs). Additional overlapping clones were identified by searching the database of available restriction fingerprints for the RPCI-23 and RPCI-24 libraries. This effort resulted in the selection of >600 BAC clones, 251 kb of BAC-end sequences, and the placement of 40 known and/or predicted genes within this 5-Mb region. We use this high-resolution map to illustrate the integration of the BAC fingerprint map with a radiation-hybrid map via assembled expressed sequence tags (ESTs). From annotation of three representative BAC clones we demonstrate that up to 98% of the draft sequence for each contig could be ordered and oriented using known genes...

‣ The Role of GABRA2 in Alcohol Dependence, Smoking and Illicit Drug Use in an Australian Population Sample

Lind, Penelope A; Macgregor, Stuart; Agrawal, Arpana; Montgomery, Grant W; Heath, Andrew C; Martin, Nicholas G; Whitfield, John B
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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‣ The Role of GABAA Receptors in the Development of Alcoholism

Enoch, Mary-Anne
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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Alcoholism is a common, heritable, chronic relapsing disorder. GABAA receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABAA receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABAA receptors: tolerance is associated with generally decreased GABAA receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABAA receptors may be implicated in the switch from heavy drinking to dependence. GABAA receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABAA receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABAA receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review.

‣ Role of GABRA2 in Trajectories of Externalizing Behavior Across Development and Evidence of Moderation by Parental Monitoring

Dick, Danielle M.; Latendresse, Shawn J.; Lansford, Jennifer E.; Budde, John P.; Goate, Alison; Dodge, Kenneth A.; Pettit, Gregory S.; Bates, John E.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/2009 Português
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‣ Uncovering genes for cognitive (dys)function and predisposition for alcoholism spectrum disorders: A review of human brain oscillations as effective endophenotypes

Rangaswamy, Madhavi; Porjesz, Bernice
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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Brain oscillations provide a rich source of potentially useful endophenotypes (intermediate phenotypes) for psychiatric genetics, as they represent important correlates of human information processing and are associated with fundamental processes from perception to cognition. These oscillations are highly heritable, are modulated by genes controlling neurotransmitters in the brain, and provide links to associative and integrative brain functions. These endophenotypes represent traits that are less complex and more proximal to gene function than either diagnostic labels or traditional cognitive measures, providing a powerful strategy in searching for genes in psychiatric disorders. These intermediate phenotypes identify both affected and unaffected members of an affected family, including offspring at risk, providing a more direct connection with underlying biological vulnerability. Our group has utilized heritable neurophysiological features (i.e., brain oscillations) as endophenotypes, making it possible to identify susceptibility genes that may be difficult to detect with diagnosis alone. We have discussed our findings of significant linkage and association between brain oscillations and genes in GABAergic, cholinergic and glutamatergic systems (GABRA2...

‣ GABRR1 and GABRR2, encoding the GABA-A receptor subunits ρ1 and ρ2, are associated with alcohol dependence

Xuei, Xiaoling; Flury-Wetherill, Leah; Dick, Danielle; Goate, Alison; Tischfield, Jay; Nurnberger, John; Schuckit, Marc; Kramer, John; Kuperman, Sam; Hesselbrock, Victor; Porjesz, Bernice; Foroud, Tatiana; Edenberg, Howard J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 05/03/2010 Português
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The genes encoding several GABA-A receptor subunits, including GABRA2, have been associated with alcoholism, suggesting that variations in GABA signaling contribute to risk. Therefore, as part of a comprehensive evaluation of the GABA receptor genes, we evaluated the potential association of GABRR1 and GABRR2, which encode the ρ1 and ρ2 subunits of the pentameric GABA-A/GABA-C receptors. GABRR1 and GABRR2 lie in a head to tail orientation spanning 137 kb on chromosome 6q14-16. We genotyped 73 SNPs, covering both genes and extending 31 kb upstream of GABRR2 and 95 kb downstream of GABRR1, in a sample of 1923 European Americans from 219 multiplex alcohol dependent families. Family-based association analyses demonstrated that SNPs in both GABRR1 and GABRR2 were significantly associated with alcohol dependence. Among the associated SNPs was rs282129, a coding SNP (Met430Thr) in GABRR2. Secondary analysis using a median split for age of onset suggests that the association is strongest when the analysis is focused upon those with earlier onset of alcohol dependence. Haplotypes in each gene were significantly overtransmitted to family members who did not meet criteria for alcohol dependence (p<0.04), and a haplotype in GABRR2 was significantly overtransmitted to family members who met a broader definition of alcoholism (p=0.002) as well as DSM-IV dependence (p=0.04).

‣ Cocaine effects on mouse incentive-learning and human addiction are linked to α2 subunit-containing GABAA receptors

Dixon, Claire I.; Morris, Hannah V.; Breen, Gerome; Desrivieres, Sylvane; Jugurnauth, Sarah; Steiner, Rebecca C.; Vallada, Homero; Guindalini, Camila; Laranjeira, Ronaldo; Messas, Guilherme; Rosahl, Thomas W.; Atack, John R.; Peden, Dianne R.; Belelli, De
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
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Because GABAA receptors containing α2 subunits are highly represented in areas of the brain, such as nucleus accumbens (NAcc), frontal cortex, and amygdala, regions intimately involved in signaling motivation and reward, we hypothesized that manipulations of this receptor subtype would influence processing of rewards. Voltage-clamp recordings from NAcc medium spiny neurons of mice with α2 gene deletion showed reduced synaptic GABAA receptor-mediated responses. Behaviorally, the deletion abolished cocaine’s ability to potentiate behaviors conditioned to rewards (conditioned reinforcement), and to support behavioral sensitization. In mice with a point mutation in the benzodiazepine binding pocket of α2-GABAA receptors (α2H101R), GABAergic neurotransmission in medium spiny neurons was identical to that of WT (i.e., the mutation was silent), but importantly, receptor function was now facilitated by the atypical benzodiazepine Ro 15-4513 (ethyl 8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate). In α2H101R, but not WT mice, Ro 15-4513 administered directly into the NAcc-stimulated locomotor activity, and when given systemically and repeatedly, induced behavioral sensitization. These data indicate that activation of α2−GABAA receptors (most likely in NAcc) is both necessary and sufficient for behavioral sensitization. Consistent with a role of these receptors in addiction...

‣ The Influence of GABRA2, Childhood Trauma and their Interaction on Alcohol, Heroin and Cocaine Dependence

Enoch, Mary-Anne; Hodgkinson, Colin A; Yuan, Qiaoping; Shen, Pei-Hong; Goldman, David; Roy, Alec
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/01/2010 Português
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‣ Loss of Ethanol Conditioned Taste Aversion and Motor Stimulation in Knockin Mice with Ethanol-Insensitive α2-Containing GABAA Receptors

Blednov, Y. A.; Borghese, C. M.; McCracken, M. L.; Benavidez, J. M.; Geil, C. R.; Osterndorff-Kahanek, E.; Werner, D. F.; Iyer, S.; Swihart, A.; Harrison, N. L.; Homanics, G. E.; Harris, R. A.
Fonte: The American Society for Pharmacology and Experimental Therapeutics Publicador: The American Society for Pharmacology and Experimental Therapeutics
Tipo: Artigo de Revista Científica
Publicado em /01/2011 Português
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GABA type A receptors (GABAA-Rs) are potential targets of ethanol. However, there are multiple subtypes of this receptor, and, thus far, individual subunits have not been definitively linked with specific ethanol behavioral actions. Interestingly, though, a chromosomal cluster of four GABAA-R subunit genes, including α2 (Gabra2), was associated with human alcoholism (Am J Hum Genet 74:705–714, 2004; Pharmacol Biochem Behav 90:95–104, 2008; J Psychiatr Res 42:184–191, 2008). The goal of our study was to determine the role of receptors containing this subunit in alcohol action. We designed an α2 subunit with serine 270 to histidine and leucine 277 to alanine mutations that was insensitive to potentiation by ethanol yet retained normal GABA sensitivity in a recombinant expression system. Knockin mice containing this mutant subunit were tested in a range of ethanol behavioral tests. These mutant mice did not develop the typical conditioned taste aversion in response to ethanol and showed complete loss of the motor stimulant effects of ethanol. Conversely, they also demonstrated changes in ethanol intake and preference in multiple tests. The knockin mice showed increased ethanol-induced hypnosis but no difference in anxiolytic effects or recovery from acute ethanol-induced motor incoordination. Overall...

‣ Variation in GABRA2 Predicts Drinking Behavior in Project MATCH Subjects

Bauer, Lance O.; Covault, Jonathan; Harel, Ofer; Das, Sourish; Gelernter, Joel; Anton, Raymond; Kranzler, Henry R.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/2007 Português
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‣ GABRG1 and GABRA2 Variation Associated with Alcohol Dependence in African Americans

Ittiwut, Chupong; Yang, Bao-Zhu; Kranzler, Henry R.; Anton, Raymond F.; Hirunsatit, Rungnapa; Weiss, Roger D.; Covault, Jonathan; Farrer, Lindsay A.; Gelernter, Joel
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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‣ The Role of the GABRA2 Polymorphism in Multiplex Alcohol Dependence Families With Minimal Comorbidity: Within-Family Association and Linkage Analyses*

MATTHEWS, ABIGAIL G.; HOFFMAN, ERIC K.; ZEZZA, NICHOLAS; STIFFLER, SCOTT; HILL, SHIRLEY Y.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/2007 Português
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‣ Association of childhood trauma exposure and GABRA2 polymorphisms with risk of posttraumatic stress disorder in adults

Nelson, Elliot C.; Agrawal, Arpana; Pergadia, Michele L.; Lynskey, Michael T.; Todorov, Alexandre A.; Wang, Jen C.; Todd, Richard D.; Martin, Nicholas G.; Heath, Andrew C.; Goate, Alison M.; Montgomery, Grant W.; Madden, Pamela A.F.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /03/2009 Português
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‣ GABRA2 and KIBRA Genotypes Predict Early Relapse to Substance Use

Bauer, L.O.; Covault, J.; Gelernter, J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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‣ Complex Control of GABA(A) Receptor Subunit mRNA Expression: Variation, Covariation, and Genetic Regulation

Mulligan, Megan K.; Wang, Xusheng; Adler, Adrienne L.; Mozhui, Khyobeni; Lu, Lu; Williams, Robert W.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 10/04/2012 Português
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GABA type-A receptors are essential for fast inhibitory neurotransmission and are critical in brain function. Surprisingly, expression of receptor subunits is highly variable among individuals, but the cause and impact of this fluctuation remains unknown. We have studied sources of variation for all 19 receptor subunits using massive expression data sets collected across multiple brain regions and platforms in mice and humans. Expression of Gabra1, Gabra2, Gabrb2, Gabrb3, and Gabrg2 is highly variable and heritable among the large cohort of BXD strains derived from crosses of fully sequenced parents—C57BL/6J and DBA/2J. Genetic control of these subunits is complex and highly dependent on tissue and mRNA region. Remarkably, this high variation is generally not linked to phenotypic differences. The single exception is Gabrb3, a locus that is linked to anxiety. We identified upstream genetic loci that influence subunit expression, including three unlinked regions of chromosome 5 that modulate the expression of nine subunits in hippocampus, and that are also associated with multiple phenotypes. Candidate genes within these loci include, Naaa, Nos1, and Zkscan1. We confirmed a high level of coexpression for subunits comprising the major channel—Gabra1...

‣ Genome-Wide Association for Fear Conditioning in an Advanced Intercross Mouse Line

Parker, Clarissa C.; Sokoloff, Greta; Cheng, Riyan; Palmer, Abraham A.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Fear conditioning (FC) may provide a useful model for some components of post-traumatic stress disorder (PTSD). We used a C57BL/6J × DBA/2J F2 intercross (n = 620) and a C57BL/6J × DBA/2J F8 advanced inter-cross line (n = 567) to fine-map quantitative trait loci (QTL) associated with FC. We conducted an integrated genome-wide association analysis in QTLRel and identified five highly significant QTL affecting freezing to context as well as four highly significant QTL associated with freezing to cue. The average percent decrease in QTL width between the F2 and the integrated analysis was 59.2%. Next, we exploited bioinformatic sequence and expression data to identify candidate genes based on the existence of non-synonymous coding polymorphisms and/or expression QTLs. We identified numerous candidate genes that have been previously implicated in either fear learning in animal models (Bcl2, Btg2, Dbi, Gabr1b, Lypd1, Pam and Rgs14) or PTSD in humans (Gabra2, Oprm1 and Trkb); other identified genes may represent novel findings. The integration of F2 and AIL data maintains the advantages of studying FC in model organisms while significantly improving resolution over previous approaches.

‣ GABRA2 MARKERS MODERATE THE SUBJECTIVE EFFECTS OF ALCOHOL

Uhart, Magdalena; Weerts, Elise M; McCaul, Mary E; Guo, Xiuqing; Yan, Xiaofei; Kranzler, Henry R; Li, Ning; Wand, Gary S
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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‣ Role of GABRA2 in Moderating Subjective Responses to Alcohol

Roh, Sungwon; Matsushita, Sachio; Hara, Sachiko; Maesato, Hitoshi; Matsui, Toshifumi; Suzuki, Go; Miyakawa, Tomohiro; Ramchandani, Vijay A.; Li, Ting-Kai; Higuchi, Susumu
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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‣ α2-containing GABAA receptors: A target for the development of novel treatment strategies for CNS disorders

Engin, Elif; Liu, Jing; Rudolph, Uwe
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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GABAA receptors have important physiological functions, as revealed by pharmacological studies and experiments involving gene-targeted mouse models, and are the target of widely used drugs such as the benzodiazepines. In this review, we are summarizing current knowledge about the function of α2-containing GABAA receptors, a receptor subtype representing approximately 15–20% of all GABAA receptors. This receptor subtype mediates anxiolytic-like, reward-enhancing, and antihyperalgesic actions of diazepam, and has antidepressant-like properties. Secondary insufficiency of α2-containing GABAA receptors has been postulated to play a role in the pathogenesis of schizophrenia, and may be involved in cognitive impairment in other disorders. Moreover, polymorphisms in the GABRA2 gene encoding the GABAA receptor α2 subunit have been found to be linked to chronic alcohol dependence and to polydrug abuse. Thus, α2-containing GABAA receptors are involved in the regulation and/or modulation of emotional behaviors and of chronic pain, and appear to be a valid target for novel therapeutic approaches for the treatment of anxiety, depression, schizophrenia and chronic pain.

‣ Pharmacogenetics of Alcohol and Alcohol Dependence Treatment

Kranzler, Henry R.; Edenberg, Howard J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em //2010 Português
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In this article, we review studies of genetic moderators of the response to medications to treat alcohol dependence, the acute response to alcohol, and the response to the psychotherapeutic treatment of heavy drinking. We consider four neurotransmitter systems: opioidergic, dopaminergic, GABAergic, and glutamatergic and focus on one receptor protein in each: OPRM1 (the μ-opioid receptor gene), DRD4 (the D4 dopamine receptor gene), GABRA2 (GABAA receptor α-2 subunit gene), and GRIK1 (the kainite receptor GluR5 subunit gene). We conclude that because parallel developments in alcoholism treatment and the genetics of alcohol dependence are beginning to converge, using genotypic information, it may be possible to match patients with specific treatments. Of greatest clinical relevance is the finding that the presence of an Asp40 allele in OPRM1 modestly predicts a better response to naltrexone treatment. Promising findings include the observations that a polymorphism in GABRA2 predicts the response to specific psychotherapies; a polymorphism in DRD4 predicts the effects of the antipsychotic olanzapine on craving for alcohol and drinking behavior; and a polymorphism in GRIK1 predicts adverse events resulting from treatment with the anticonvulsant topiramate. Although variants in other genes have been associated with the risk for alcohol dependence...