Article

Association of galanin haplotypes with alcoholism and anxiety in two ethnically distinct populations

Pain and Neurosensory Mechanisms Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD 20892, USA.
Molecular Psychiatry (Impact Factor: 15.15). 03/2006; 11(3):301-11. DOI: 10.1038/sj.mp.4001768
Source: PubMed

ABSTRACT The neuropeptide galanin (GAL) is widely expressed in the central nervous system. Animal studies have implicated GAL in alcohol abuse and anxiety: chronic ethanol intake increases hypothalamic GAL mRNA; high levels of stress increase GAL release in the central amygdala. The coding sequence of the galanin gene, GAL, is highly conserved and a functional polymorphism has not yet been found. The aim of our study was, for the first time, to identify GAL haplotypes and investigate associations with alcoholism and anxiety. Seven single-nucleotide polymorphisms (SNPs) spanning GAL were genotyped in 65 controls from five populations: US and Finnish Caucasians, African Americans, Plains and Southwestern Indians. A single haplotype block with little evidence of historical recombination was observed for each population. Four tag SNPs were then genotyped in DSM-III-R lifetime alcoholics and nonalcoholics from two population isolates: 514 Finnish Caucasian men and 331 Plains Indian men and women. Tridimensional Personality Questionnaire harm avoidance (HA) scores, a dimensional measure of anxiety, were obtained. There was a haplotype association with alcoholism in both the Finnish (P=0.001) and Plains Indian (P=0.004) men. The SNPs were also significantly associated. Alcoholics were divided into high and low HA groups (>or= and <mean HA of population). In the Finns, haplotype (P<0.0001) and diplotype (P<0.0001) distributions differed between high HA alcoholics, low HA alcoholics and nonalcoholics. Our results from two independent populations suggest that GAL may contribute to vulnerability to alcoholism, perhaps mediated by dimensional anxiety.

Download full-text

Full-text

Available from: Inna Belfer, Aug 30, 2015
0 Followers
 · 
100 Views
  • Source
    • "In Finnish and American Plains Indian men , an association of GAL haplotypes with alcoholism has been reported ( Belfer et al . , 2006 ) . Furthermore , the GAL 3 gene , but not the GAL 1 and GAL 2 genes , was associated with alcoholism in Finnish Caucasians ( Belfer et al . , 2007 ) , whereas in the same study , no association of the GAL 3 locus with alcoholism was observed in American Plains Indians . This difference"
    [Show abstract] [Hide abstract]
    ABSTRACT: Galanin was first identified 30 years ago as a "classic neuropeptide," with actions primarily as a modulator of neurotransmission in the brain and peripheral nervous system. Other structurally-related peptides-galanin-like peptide and alarin-with diverse biologic actions in brain and other tissues have since been identified, although, unlike galanin, their cognate receptors are currently unknown. Over the last two decades, in addition to many neuronal actions, a number of nonneuronal actions of galanin and other galanin family peptides have been described. These include actions associated with neural stem cells, nonneuronal cells in the brain such as glia, endocrine functions, effects on metabolism, energy homeostasis, and paracrine effects in bone. Substantial new data also indicate an emerging role for galanin in innate immunity, inflammation, and cancer. Galanin has been shown to regulate its numerous physiologic and pathophysiological processes through interactions with three G protein-coupled receptors, GAL1, GAL2, and GAL3, and signaling via multiple transduction pathways, including inhibition of cAMP/PKA (GAL1, GAL3) and stimulation of phospholipase C (GAL2). In this review, we emphasize the importance of novel galanin receptor-specific agonists and antagonists. Also, other approaches, including new transgenic mouse lines (such as a recently characterized GAL3 knockout mouse) represent, in combination with viral-based techniques, critical tools required to better evaluate galanin system physiology. These in turn will help identify potential targets of the galanin/galanin-receptor systems in a diverse range of human diseases, including pain, mood disorders, epilepsy, neurodegenerative conditions, diabetes, and cancer. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
    Pharmacological reviews 01/2015; 67(1):118-175. DOI:10.1124/pr.112.006536 · 18.55 Impact Factor
  • Source
    • "These include metabolism , feeding and endocrinology, cognition, epilepsy, chronic anxiety and depression, addiction, neuroprotection, neuronal regeneration, and pain (see recent reviews (Lang et al., 2007; Ogren et al., 2010; Picciotto et al., 2010)). Some, but by no means all, of these rodent findings are paralleled by human studies demonstrating associations between single nucleotide polymorphisms (SNPs) in the GAL gene and/or one of its three receptors, and depression or anxiety disorders (Unschuld et al., 2008; Wray et al., 2010; Juhasz et al., 2014) and addictive behaviours that include smoking (Gold et al., 2012), alcohol (Belfer et al., 2006), and heroin (Levran et al., 2008). To date, there are no studies that link the galaninergic system to dietary fat intake or weight regulation in humans, though a single study has shown a relationship with elevated triglyceride levels in familial combined hyperlipidaemia (Plaisier et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: There is a large body of pre-clinical and some clinical data to link the neuropeptide galanin to a range of physiological and pathological functions that include metabolism, depression, and addiction. An enhancer region upstream of the human GAL transcriptional start site has previously been characterised. In-vitro transfection studies in rat hypothalamic neurons demonstrated that the CA allele was 40% less active than the GG allele in driving galanin expression. Our hypothesis was to investigate the effect of this galanin enhancer genotype on a range of variables that relate to the known functions of the galaninergic system in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort of young adults (N = 169–6,078). Initial findings showed a positive relationship of cannabis usage (OR = 2.070, P = 0.007, N = 406 (individuals who had used cannabis at least once within the last 12 months, total sample size 2731) with the GG haplotype, consistent with the previous published data linking galanin with an increased release of dopamine. As our sample size was relatively small we replicated the analysis in a larger cohort of 2,224 African Americans and 1,840 European Americans, but no discernible trend across genotypes was observed for the relationship with cannabis usage. Further, we found no association of the galanin enhancer genotype with any of the other pathophysiological parameters measured. These findings emphasise that preclinical data does not always predict clinical outcomes in cohort studies, noting that association studies are subject to multiple confounders. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2014; 165(8). DOI:10.1002/ajmg.b.32270 · 3.27 Impact Factor
  • Source
    • "In addition to these neurotransmitters, there are a number of orexigenic peptides, which in rodents are found to stimulate the consumption of ethanol and to be strongly affected by ethanol [18] [19] [20] [21] and in humans are believed to have a role in alcoholism [22] [23]. These include galanin (GAL) and orexin/hypocretin (OX), which shows increased expression in rats administered or trained to drink ethanol [19] [20] [24] and higher expression in inbred and outbred rodent strains that spontaneously overconsume ethanol [25] [26]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies in zebrafish have shown that exposure to ethanol in tank water affects various behaviors, including locomotion, anxiety and aggression, and produces changes in brain neurotransmitters, such as serotonin and dopamine. Building on these investigations, the present study had two goals: first, to develop a method for inducing voluntary ethanol intake in individual zebrafish, which can be used as a model in future studies to examine how this behavior is affected by various manipulations, and second, to characterize the effects of this ethanol intake on different behaviors and the expression of hypothalamic orexigenic peptides, galanin (GAL) and orexin (OX), which are known in rodents to stimulate consumption of ethanol and alter behaviors associated with alcohol abuse. Thus, we first developed a new model of voluntary intake of ethanol in fish by presenting this ethanol mixed with gelatin, which they readily consume. Using this model, we found that individual zebrafish can be trained in a short period to consume stable levels of 10% or 20% ethanol (v/v) mixed with gelatin and that their intake of this ethanol-gelatin mixture leads to pharmacologically relevant blood ethanol concentrations which are strongly, positively correlated with the amount ingested. Intake of this ethanol-gelatin mixture increased locomotion, reduced anxiety, and stimulated aggressive behavior, while increasing expression of GAL and OX in specific hypothalamic areas. These findings, confirming results in rats, provide a method in zebrafish for investigating with forward genetics and pharmacological techniques the role of different brain mechanisms in controlling ethanol intake.
    Behavioural Brain Research 09/2014; 278. DOI:10.1016/j.bbr.2014.09.024 · 3.39 Impact Factor
Show more