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

Qiu B1, Luczak SE2, Wall TL3,4,5, Kirchhoff AM6, Xu Y7, Eng MY8, Stewart RB9, Shou W10, Boehm SL11, Chester JA12, Yong W13,14, Liang T15.

Author information

1Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS), Peking Union Medical College (PUMC), Beijing 100021, China. qiub@cnilas.org.

2Department of Psychology, University of Southern California, Los Angeles, CA 90089, USA. luczak@usc.edu.

3Department of Psychiatry, University of California, San Diego, CA 92037, USA. twall@ucsd.edu.

4Psychology Service, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA. twall@ucsd.edu.

5Veterans Medical Research Foundation, San Diego, CA 92161, USA. twall@ucsd.edu.

6Immunology and Microbial Science Department, Research Technician, The Scripps Research Institute, Scripps Clinic South Driveway, La Jolla, CA 92037, USA. amkirchhoff@gmail.com.

7Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS), Peking Union Medical College (PUMC), Beijing 100021, China. xuyuxue1127@gmail.com.

8Veterans Medical Research Foundation, San Diego, CA 92161, USA. mimyeng@stanfordalumni.org.

9Department of Psychology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA. rstewart@iupui.edu.

10Departments of Pediatrics and Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. wshou@iu.edu.

11Department of Psychology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA. slboehm@iupui.edu.

12Department of Psychological Sciences, Purdue University, West Lafayette, IN 47907, USA. jchester@psych.purdue.edu.

13Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS), Peking Union Medical College (PUMC), Beijing 100021, China. wyong@cnilas.org.

14Departments of Pediatrics and Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. wyong@cnilas.org.

15Department of Medicine, Indiana University School of Medicine Gatch Hall, Indianapolis, IN 46202, USA. tliang@iu.edu.

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 Fkbp5knockout (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.

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