Publications by authors named "Xavier Gallego"

9 Publications

  • Page 1 of 1

Functional characterization of SNPs in CHRNA3/B4 intergenic region associated with drug behaviors.

Brain Res 2013 Sep 18;1529:1-15. Epub 2013 Jul 18.

Institute for Behavioral Genetics, University of Colorado Boulder, 1480 30th Street, Boulder, CO 80303, USA.

The cluster of human neuronal nicotinic receptor genes (CHRNA5/A3/B4) (15q25.1) has been associated with a variety of smoking and drug-related behaviors, as well as risk for lung cancer. CHRNA3/B4 intergenic single nucleotide polymorphisms (SNPs) rs1948 and rs8023462 have been associated with early initiation of alcohol and tobacco use, and rs6495309 has been associated with nicotine dependence and risk for lung cancer. An in vitro luciferase expression assay was used to determine whether these SNPs and surrounding sequences contribute to differences in gene expression using cell lines either expressing proteins characteristic of neuronal tissue or derived from lung cancers. Electrophoretic mobility shift assays (EMSAs) were performed to investigate whether nuclear proteins from these cell lines bind SNP alleles differentially. Results from expression assays were dependent on cell culture type and haplotype. EMSAs indicated that rs8023462 and rs6495309 bind nuclear proteins in an allele-specific way. Additionally, GATA transcription factors appeared to bind rs8023462 only when the minor/risk allele was present. Much work has been done to describe the rat Chrnb4/a3 intergenic region, but few studies have examined the human intergenic region effects on expression; therefore, these studies greatly aid human genetic research as it relates to observed nicotine phenotypes, lung cancer risk and potential underlying genetic mechanisms. Data from these experiments support the hypothesis that SNPs associated with human addiction-related phenotypes and lung cancer risk can affect gene expression, and are potential therapeutic targets. Additionally, this is the first evidence that rs8023462 interacts with GATA transcription factors to influence gene expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainres.2013.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839343PMC
September 2013

Alternative CHRNB4 3'-UTRs mediate the allelic effects of SNP rs1948 on gene expression.

PLoS One 2013 14;8(5):e63699. Epub 2013 May 14.

Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado, USA.

Common genetic factors strongly contribute to both nicotine, the main addictive component of tobacco, and alcohol use. Several lines of evidence suggest nicotinic acetylcholine receptors as common sites of action for nicotine and alcohol. Specifically, rs1948, a single-nucleotide polymorphism (SNP) located in the CHRNB4 3'-untranslated region (UTR), has been associated to early age of initiation for both alcohol and tobacco use. To determine the allelic effects of rs1948 on gene expression, two rs1948-containing sequences of different lengths corresponding to the CHRNB4 3'-UTR were cloned into pGL3-promoter luciferase reporter vectors. Data obtained showed that the allelic effects of SNP rs1948 on luciferase expression are mediated by the length and species of transcripts generated. In addition, it was found that miR-3157 increased the overall luciferase expression while miR-138, a microRNA known to play a role in neuroadaptation to drug abuse, decreased luciferase expression when compared to basal conditions. These findings demonstrate the importance of SNP rs1948 on the regulation of CHRNB4 expression and provide the first evidence of CHRNB4 down-regulation by miR-138.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063699PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653846PMC
December 2013

Transgenic over expression of nicotinic receptor alpha 5, alpha 3, and beta 4 subunit genes reduces ethanol intake in mice.

Alcohol 2012 May 27;46(3):205-15. Epub 2012 Mar 27.

Genes and Disease Program, Center for Genomic Regulation, UPF, Barcelona, Spain.

Abuse of alcohol and smoking are extensively co-morbid. Some studies suggest partial commonality of action of alcohol and nicotine mediated through nicotinic acetylcholine receptors (nAChRs). We tested mice with transgenic over expression of the alpha 5, alpha 3, beta 4 receptor subunit genes, which lie in a cluster on human chromosome 15, that were previously shown to have increased nicotine self-administration, for several responses to ethanol. Transgenic and wild-type mice did not differ in sensitivity to several acute behavioral responses to ethanol. However, transgenic mice drank less ethanol than wild-type in a two-bottle (ethanol vs. water) preference test. These results suggest a complex role for this receptor subunit gene cluster in the modulation of ethanol's as well as nicotine's effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.alcohol.2011.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340912PMC
May 2012

Overexpression of the CHRNA5/A3/B4 genomic cluster in mice increases the sensitivity to nicotine and modifies its reinforcing effects.

Amino Acids 2012 Aug 19;43(2):897-909. Epub 2011 Nov 19.

Genes and Disease Program, Center for Genomic Regulation, Barcelona Biomedical Research Park, 08003 Barcelona, Catalonia, Spain.

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated pentameric ion channels that account for the effects of nicotine. Recent genetic studies have highlighted the importance of variants of the CHRNA5/A3/B4 genomic cluster in human nicotine dependence. Among these genetic variants those found in non-coding segments of the cluster may contribute to the pathophysiology of tobacco use through alterations in the expression of these genes. To discern the in vivo effects of the cluster, we generated a transgenic mouse overexpressing the human CHRNA5/A3/B4 cluster using a bacterial artificial chromosome. Transgenic mice showed increased functional α3β4-nAChRs in brain regions where these subunits are highly expressed under normal physiological conditions. Moreover, they exhibited increased sensitivity to the pharmacological effects of nicotine along with higher activation of the medial habenula and reduced activation of dopaminergic neurons in the ventral tegmental area after acute nicotine administration. Importantly, transgenic mice showed increased acquisition of nicotine self-administration (0.015 mg/kg per infusion) and a differential response in the progressive ratio test. Our study provides the first in vivo evidence of the involvement of the CHRNA5/A3/B4 genomic cluster in nicotine addiction through modifying the activity of brain regions responsible for the balance between the rewarding and the aversive properties of this drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00726-011-1149-yDOI Listing
August 2012

Overexpression of α3/α5/β4 nicotinic receptor subunits modifies impulsive-like behavior.

Drug Alcohol Depend 2012 May 22;122(3):247-52. Epub 2011 Oct 22.

Laboratory of Neuropharmacology, Pompeu Fabra University, PRBB, Barcelona, Spain.

Recent studies have revealed that sequence variants in genes encoding the α3/α5/β4 nicotinic acetylcholine receptor subunits are associated with nicotine dependence. In this study, we evaluated two specific aspects of executive functioning related to drug addiction (impulsivity and working memory) in transgenic mice over expressing α3/α5/β4 nicotinic receptor subunits. Impulsivity and working memory were evaluated in an operant delayed alternation task, where mice must inhibit responding between 2 and 8s in order to receive food reinforcement. Working memory was also evaluated in a spontaneous alternation task in an open field. Transgenic mice showed less impulsive-like behavior than wild-type controls, and this behavioral phenotype was related to the number of copies of the transgene. Thus, transgenic Line 22 (16-28 copies) showed a more pronounced phenotype than Line 30 (4-5 copies). Overexpression of these subunits in Line 22 reduced spontaneous alternation behavior suggesting deficits in working memory processing in this particular paradigm. These results reveal the involvement of α3/α5/β4 nicotinic receptor subunits in working memory and impulsivity, two behavioral traits directly related to the vulnerability to develop nicotine dependence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.drugalcdep.2011.09.027DOI Listing
May 2012

Increased opioid dependence in a mouse model of panic disorder.

Front Behav Neurosci 2010 22;3:60. Epub 2010 Feb 22.

Genes and Disease Program, Genomic Regulation Center-CRG, Barcelona Biomedical Research Park-PRBB and CIBER de Enfermedades Raras Barcelona, Catalonia, Spain.

Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high-affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3). Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met(5)-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/neuro.08.060.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831706PMC
July 2011

Susceptibility to stress in transgenic mice overexpressing TrkC, a model of panic disorder.

J Psychiatr Res 2010 Feb 20;44(3):157-67. Epub 2009 Aug 20.

Genes and Disease Program, Centre for Genomic Regulation, Universidad Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), Dr. Aiguader 88, Barcelona E-08003, Spain.

Stressful life events increase the susceptibility for subsequent onset of psychiatric disorders in humans. Previous research has implicated neurotrophins in the onset of some stress-related diseases, such as major depression disorder, post-traumatic stress disorder or panic disorder. We have tested the hypothesis that the neurotrophin-3 (NT-3)/TrkC system is a genetic interface mediating the deleterious effects of stress on the initiation of panic disorder and other pathologies. To this aim, we have analyzed the functionality of HPA axis and the behavioral consequences of different types of stressful conditions in a mouse model of panic disorder, which overexpresses TrkC, the high affinity-receptor for NT-3 (TgNTRK3). Our results reveal that TgNTRK3 mice exhibit an altered circadian corticosterone rhythm that is reversed by clonidine treatment, but normal expression of genes involved in the control of the hypothalamus-pituitary-adrenal (HPA) axis (CRH, GR) and normal corticosterone response to acute and chronic stressors. In contrast, they exhibit an altered pattern of activation of stress-related brain areas and showed enhanced anxiety-related behavior and more passive strategies than wild types under some chronic stress conditions. We conclude that TgNTRK3 mice present differences in their response to stress characterized by subtle changes in the HPA axis, marked changes in acute stress-induced brain activation and altered coping strategies, suggesting a key role of TrkC receptor in the stress neural circuitry and in the behavioral consequences of chronic stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychires.2009.07.008DOI Listing
February 2010

Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders.

Hum Mol Genet 2008 May 18;17(9):1234-44. Epub 2008 Jan 18.

Genes and Disease Program, Center for Genomic Regulation, 08003 Barcelona, Catalonia, Spain.

Eating disorders (EDs) are complex psychiatric diseases that include anorexia nervosa and bulimia nervosa, and have higher than 50% heritability. Previous studies have found association of BDNF and NTRK2 to ED, while animal models suggest that other neurotrophin genes might also be involved in eating behavior. We have performed a family-based association study with 151 TagSNPs covering 10 neurotrophin signaling genes: NGFB, BDNF, NTRK1, NGFR/p75, NTF4/5, NTRK2, NTF3, NTRK3, CNTF and CNTFR in 371 ED trios of Spanish, French and German origin. Besides several nominal associations, we found a strong significant association after correcting for multiple testing (P = 1.04 x 10(-4)) between ED and rs7180942, located in the NTRK3 gene, which followed an overdominant model of inheritance. Interestingly, HapMap unrelated individuals carrying the rs7180942 risk genotypes for ED showed higher levels of expression of NTRK3 in lymphoblastoid cell lines. Furthermore, higher expression of the orthologous murine Ntrk3 gene was also detected in the hypothalamus of the anx/anx mouse model of anorexia. Finally, variants in NGFB gene appear to modify the risk conferred by the NTRK3 rs7180942 risk genotypes (P = 4.0 x 10(-5)) showing a synergistic epistatic interaction. The reported data, in addition to the previous reported findings for BDNF and NTRK2, point neurotrophin signaling genes as key regulators of eating behavior and their altered cross-regulation as susceptibility factors for EDs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddn013DOI Listing
May 2008

Transgenic mice overexpressing the full-length neurotrophin receptor TrkC exhibit increased catecholaminergic neuron density in specific brain areas and increased anxiety-like behavior and panic reaction.

Neurobiol Dis 2006 Nov 11;24(2):403-18. Epub 2006 Sep 11.

Genes and Disease Program, Genomic Regulation Center (CRG-UPF), Barcelona, Biomedical Research Park, E-08003 Barcelona, Catalonia, Spain.

Accumulating evidence has suggested that neurotrophins participate in the pathophysiology of mood disorders. We have developed transgenic mice overexpressing the full-length neurotrophin-3 receptor TrkC (TgNTRK3) in the central nervous system. TgNTRK3 mice show increased anxiety-like behavior and enhancement of panic reaction in the mouse defense test battery, along with an increase in the number and density of catecholaminergic (tyrosine hydroxylase positive) neurons in locus coeruleus and substantia nigra. Furthermore, treatment of TgNTRK3 mice with diazepam significantly attenuated the anxiety-like behaviors in the plus maze. These results provide evidence for the involvement of TrkC in the development of noradrenergic neurons in the central nervous system with consequences on anxiety-like behavior and panic reaction. Thus, changes in TrkC expression levels could contribute to the phenotypic expression of panic disorder through a trophic effect on noradrenergic neurons in the locus coeruleus. Our results demonstrate that the elevated NT3-TrkC tone via overexpression of TrkC in the brain may constitute a molecular mechanism for the expression of anxiety and anxiety.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2006.07.015DOI Listing
November 2006
-->