Dataset Information

The FKBP5 Gene Affects Alcohol Drinking in Knockout Mice and Is Implicated in Alcohol Drinking in Humans.

ABSTRACT: FKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR)-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity. The purpose of this study is to characterize alcohol preference and related phenotypes in Fkbp5 knockout (KO) mice and to examine the role of FKBP5 in human alcohol consumption. The following experiments were performed to characterize Fkpb5 KO mice. (1) Fkbp5 KO and wild-type (WT) EtOH consumption was tested using a two-bottle choice paradigm; (2) The EtOH elimination rate was measured after intraperitoneal (IP) injection of 2.0 g/kg EtOH; (3) Blood alcohol concentration (BAC) was measured after 3 h limited access of alcohol; (4) Brain region expression of Fkbp5 was identified using LacZ staining; (5) Baseline corticosterone (CORT) was assessed. Additionally, two SNPs, rs1360780 (C/T) and rs3800373 (T/G), were selected to study the association of FKBP5 with alcohol consumption in humans. Participants were college students (n = 1162) from 21-26 years of age with Chinese, Korean or Caucasian ethnicity. The results, compared to WT mice, for KO mice exhibited an increase in alcohol consumption that was not due to differences in taste sensitivity or alcohol metabolism. Higher BAC was found in KO mice after 3 h of EtOH access. Fkbp5 was highly expressed in brain regions involved in the regulation of the stress response, such as the hippocampus, amygdala, dorsal raphe and locus coeruleus. Both genotypes exhibited similar basal levels of plasma corticosterone (CORT). Finally, single nucleotide polymorphisms (SNPs) in FKBP5 were found to be associated with alcohol drinking in humans. These results suggest that the association between FKBP5 and alcohol consumption is conserved in both mice and humans.

SUBMITTER: Qiu B

PROVIDER: S-EPMC5000669 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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The FKBP5 Gene Affects Alcohol Drinking in Knockout Mice and Is Implicated in Alcohol Drinking in Humans.

Qiu Bin B Luczak Susan E SE Wall Tamara L TL Kirchhoff Aaron M AM Xu Yuxue Y Eng Mimy Y MY Stewart Robert B RB Shou Weinian W Boehm Stephen L SL Chester Julia A JA Yong Weidong W Liang Tiebing T

International journal of molecular sciences 20160805 8

FKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR)-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity. The purpose of this study is to characterize alcohol preference and related phenotypes in Fkbp5 knockout (KO) mice and to examine the role of FKBP5 in human alcohol consumption. The following experiments were performed to characterize Fkpb5 KO mice. (1) Fkbp5 KO and wild-type (WT) EtOH consumption was tested using a two-bottle choice p ...[more]

PMID: 27527158

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Project description:BackgroundImpulsivity is genetically correlated with, and precedes, addictive behaviors and alcoholism. If impulsivity or attention is causally related to addiction, certain pharmacological manipulations of impulsivity and/or attention may affect alcohol drinking, and vice versa. The current studies were designed to explore the relationship among impulsivity, drinking, and vigilance in selectively bred High Alcohol Preferring (HAP) mice, a line that has previously demonstrated both high impulsivity and high alcohol consumption. Amphetamine, naltrexone, and memantine were tested in a delay discounting (DD) task for their effects on impulsivity and vigilance. The same drugs and doses were also assessed for effects on alcohol drinking in a 2-bottle choice test.MethodsHAP mice were subjected to a modified version of adjusting amount DD using 0.5-second and 10-second delays to detect decreases and increases, respectively, in impulsive responding. In 2 experiments, mice were given amphetamine (0.4, 0.8, or 1.2 mg/kg), naltrexone (3 and 10 mg/kg), and memantine (1 and 5 mg/kg) before DD testing. Another pair of studies used scheduled access, 2-bottle choice drinking to assess effects of amphetamine (0.4, 1.2, or 3.0 mg/kg), naltrexone (3 and 10 mg/kg), and memantine (1 and 5 mg/kg) on alcohol consumption.ResultsAmphetamine dose-dependently reduced impulsivity and vigilance decrement in DD, but similar doses left alcohol drinking unaffected. Naltrexone and memantine decreased alcohol intake at doses that did not affect water drinking but had no effects on impulsivity or vigilance decrement in the DD task.ConclusionsContrary to our hypothesis, none of the drugs tested here, while effective on either alcohol drinking or impulsivity, decreased both behaviors. These findings suggest that the genetic association between drinking and impulsivity observed in this population is mediated by mechanisms other than those targeted by the drugs tested in these studies.

Project description:Background:Previous research has shown that polymorphisms in the FKBP5 gene are related to some psychiatric conditions, including alcohol dependence. These relationships are moderated by the level of adverse childhood experiences that one has undergone. Maladaptive metacognition, associated with symptoms of psychiatric disorders and disturbed emotional self-regulation, is also a strong predictor of problematic alcohol use. Recent studies suggest that maladaptive metacognitions may be part of the developmental pathway from childhood abuse to drinking problems. This study attempted to identify relationships between FKBP5 polymorphisms and metacognitions about the positive effects of alcohol use and problematic drinking in a group differing in levels of childhood trauma. Methods:The sample studied was composed of 502 female participants aged 18-25 years (M=21.78; SD=1.84). Positive metacognitions about alcohol use were measured with the Positive Alcohol Metacognitions Scale (PAMS) and problematic drinking was gauged using the WHO Alcohol Use Disorders Identification Test. Levels of childhood adverse experiences were determined with the use of the Childhood Questionnaire. A total of 18 single-nucleotide polymorphisms (SNPs) in the FKBP5 gene were genotyped. Results:We did not find any interaction between the gene and childhood trauma on problematic drinking or metacognitions. However we identified a strong main effect of two SNPs of the FKBP5 gene - rs755658 and rs1334894 - on the PAMS subscale measuring positive metacognitive beliefs about emotional self-regulation. We also found nominally significant relations of several other SNPs with metacognitions and problematic drinking. Additionally, we showed that positive alcohol metacognitions mediate the relationship between problematic drinking and both rs755658 and rs1334894. Conclusion:Our results may shed some light on the biological underpinnings of the developmental pathway leading to problematic drinking through maladaptive metacognitions.

Dataset Information

The FKBP5 Gene Affects Alcohol Drinking in Knockout Mice and Is Implicated in Alcohol Drinking in Humans.

Publications

The FKBP5 Gene Affects Alcohol Drinking in Knockout Mice and Is Implicated in Alcohol Drinking in Humans.

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