Ionotropic glutamate receptor gene GRIK3 SER310ALA functional polymorphism is related to delirium tremens in alcoholics

Preuss, U. W.; Zill, Peter; Koller, Gabriele; Bondy, Brigitta; Hesselbrock, Victor; Soyka, Michael

doi:10.1038/sj.tpj.6500343

Cited by 33 publications

(23 citation statements)

References 55 publications

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“…Findings from this study should be interpreted in light of several limitations. Previous investigations of the genetic component of alcohol withdrawal-related phenotypes have typically classified subjects as with or without a specific history of DTs, hallucinations, and seizures (Schmidt and Sander, 2000;Koehnke et al, 2002;Okubo et al, 2003;Schumann et al, 2003;Wernicke et al, 2003;Limosin et al, 2004;Rujescu et al, 2005;Tadic et al, 2005;Preuss et al, 2006;van Munster et al, 2007;Karpyak et al, 2010;Du et al, 2011). It is important to note that the withdrawal severity in our patients was generally mild to moderate, and as a result our findings cannot be extended to patients exhibiting severe forms of withdrawal.…”

Section: Discussionmentioning

confidence: 57%

“…Nevertheless, genes influencing alcohol withdrawal severity are largely unknown, except for the multiple PDZ-binding domain protein (MPDZ), which may modulate withdrawal severity both in mice (Shirley et al, 2004) and humans (Karpyak et al, 2009). Existing reports on the association of vulnerability genes with acute withdrawal severity have largely focused on specific severe phenotypes such as delirium tremens (DTs), seizures, or hallucinations (Okubo et al, 2003;Limosin et al, 2004;Rujescu et al, 2005;Tadic et al, 2005;Preuss et al, 2006;van Munster et al, 2007;Karpyak et al, 2010;Du et al, 2011), associations with high or low number of withdrawal symptoms (Schumann et al, 2003), or phenotypes categorized as mild or severe AWS (Schmidt and Sander, 2000;Koehnke et al, 2002;Schumann et al, 2003;Wernicke et al, 2003). However, the symptom profile of AWS runs on a continuum with substantial individual variation, and little is known about the potential genetic components that influence the severity of AWS in individuals who do not experience DTs or withdrawal seizures.…”

Section: Introductionmentioning

confidence: 99%

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FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

Huang

Schwandt

Chester

et al. 2014

Neuropsychopharmacol

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Alcohol withdrawal is associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction. The FKBP5 gene codes for a cochaperone, FK506-binding protein 5, that exerts negative feedback on HPA axis function. This study aimed to examine the effects of single-nucleotide polymorphisms (SNPs) of the FKBP5 gene in humans and the effect of Fkbp5 gene deletion in mice on alcohol withdrawal severity. We genotyped six FKBP5 SNPs (rs3800373, rs9296158, rs3777747, rs9380524, rs1360780, and rs9470080) in 399 alcohol-dependent inpatients with alcohol consumption 48 h before admission and recorded scores from the Clinical Institute Withdrawal Assessment-Alcohol revised (CIWA-Ar). Fkbp5 gene knockout (KO) and wild-type (WT) mice were assessed for alcohol withdrawal using handling-induced convulsions (HICs) following both acute and chronic alcohol exposure. We found the minor alleles of rs3800373 (G), rs9296158 (A), rs1360780 (T), and rs9470080 (T) were significantly associated with lower CIWA-Ar scores whereas the minor alleles of rs3777747 (G) and rs9380524 (A) were associated with higher scores. The haplotype-based analyses also showed an association with alcohol withdrawal severity. Fkbp5 KO mice showed significantly greater HICs during withdrawal from chronic alcohol exposure compared with WT controls. This study is the first to show a genetic effect of FKBP5 on the severity of alcohol withdrawal syndrome. In mice, the absence of the Fkbp5 gene enhances sensitivity to alcohol withdrawal. We suggest that FKBP5 variants may trigger different adaptive changes in HPA axis regulation during alcohol withdrawal with concomitant effects on withdrawal severity.

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Section: Discussionmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

Huang

Schwandt

Chester

et al. 2014

Neuropsychopharmacol

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“…Genetic variants in brain-derived neurotrophic factor (BDNF; Matsushita et al, 2004), cannabinoid receptor 1 (CNR1; Schmidt et al, 2002), GR ionotropic, kainate 3 (GRIK3; Preuss et al, 2006), and tyrosine hydroxylase (TH; Sander et al, 1998) could possibly influence vulnerability to DT, as there was an association found in 1 study. Alcoholic subjects with a history of DT had a significantly higher frequency of the AA genotype in the BDNF gene (21.6%), compared with alcoholic subjects without DT (13.1%, p 5 0.008; Matsushita et al, 2004).…”

Section: Resultsmentioning

confidence: 92%

Genetic Polymorphisms Related to Delirium Tremens: A Systematic Review

Munster

Korevaar

Rooij

et al. 2007

Alcoholism Clin & Exp Res

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“…Also, the facts that binge alcohol-induced neurodegeneration in rats was not reduced by the noncompetitive NMDAR antagonist, memantine (Hamelink et al, 2005), nor was it accompanied by increased brain NMDAR as ascertained with [ 3 H]MK-801 binding (Rudolph et al, 1997), further argue against a prominent excitotoxic mechanism. It is still possible, as suggested by studies of ionotropic glutamate receptors in alcoholics (Preuss et al, 2006) and reviewed by others (Tsai and Coyle, 1998), that excessive glutamatergic transmission could be involved in alcohol withdrawal seizures and disturbed autonomic activation. However, in binge alcoholintoxicated adult rats, the density of neurodegeneration reaches a maximum considerably earlier than the time of greatest seizure activity (Majchrowicz, 1975) and does not increase throughout a 36-h withdrawal period (Collins et al, (C) Significant reduction by ATZ co-treatment of argyrophilia (mean degenerating neuronal cell counts) in the entorhinal cortex and dentate gyrus of adult rats binge alcoholintoxicated once daily for 8 days.…”

Section: Alcohol Neurodamage and Brain Edemamentioning

confidence: 99%

Linking Binge Alcohol-Induced Neurodamage to Brain Edema and Potential Aquaporin-4 Upregulation: Evidence in Rat Organotypic Brain Slice Cultures andIn Vivo

Kumar¹,

Brown

Neafsey

et al. 2009

Journal of Neurotrauma

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Brain edema and derived oxidative stress potentially are critical events in the hippocampal-entorhinal cortical (HEC) neurodegeneration caused by binge alcohol (ethanol) intoxication and withdrawal in adult rats. Edema's role is based on findings that furosemide diuretic antagonizes binge alcohol-dependent brain overhydration and neurodamage in vivo and in rat organotypic HEC slice cultures. However, evidence that furosemide has significant antioxidant potential and knowledge that alcohol can cause oxidative stress through non-edemic pathways has placed edema's role in question. We therefore studied three other diuretics and a related non-diuretic that, according to our oxygen radical antioxidant capacity (ORAC) assays or the literature, possess minimal antioxidant potential. Acetazolamide (ATZ), a carbonic anhydrase inhibitor=diuretic with negligible ORAC effectiveness and, interestingly, an aquaporin-4 (AQP4) water channel inhibitor, prevented alcohol-dependent tissue edema and neurodegeneration in HEC slice cultures. Likewise, in binge alcohol-intoxicated rats, ATZ suppressed brain edema while inhibiting neurodegeneration. Torasemide, a loop diuretic lacking furosemide's ORAC capability, also prevented alcohol-induced neurodamage in HEC slice cultures. However, bumetanide (BUM), a diuretic blocker of NaÀ channels, and L-644, 711, a nondiuretic anion channel inhibitor-both lacking antioxidant capabilities as well as reportedly ineffective against alcohol-dependent brain damage in vivo-reduced neither alcohol-induced neurotoxicity nor (with BUM) edema in HEC slices. Because an AQP4 blocker (ATZ) was neuroprotective, AQP4 expression in the HEC slices was examined and found to be elevated by binge alcohol. The results further indicate that binge ethanol-induced brain edema=swelling, potentially associated with AQP4 upregulation, may be important in consequent neurodegeneration that could derive from neuroinflammatory processes, for example, membrane arachidonic acid mobilization and associated oxidative stress.

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Ionotropic glutamate receptor gene GRIK3 SER310ALA functional polymorphism is related to delirium tremens in alcoholics

Cited by 33 publications

References 55 publications

FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

Genetic Polymorphisms Related to Delirium Tremens: A Systematic Review

Linking Binge Alcohol-Induced Neurodamage to Brain Edema and Potential Aquaporin-4 Upregulation: Evidence in Rat Organotypic Brain Slice Cultures andIn Vivo

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