title: Evidence for a Link Between Fkbp5/FKBP5, Early Life Social Relations and Alcohol Drinking in Young Adult Rats and Humans.
abstract: Alcohol misuse has been linked to dysregulation of stress, emotion, and reward brain circuitries. A candidate key mediator of this association is the FK506-binding protein (FKBP5), a negative regulator of the glucocorticoid receptor. The aim of the present study was to further understand the Fkbp5/FKBP5-related genetic underpinnings underlying the relationship between early life social relations and alcohol drinking. The effect of maternal separation and voluntary alcohol drinking on Fkbp5 expression was investigated in the brain of young adult rats, whereas the interaction effect of the functional FKBP5 single nucleotide polymorphism rs1360780 genotype and parent-child relationship on problematic drinking was examined in young adult humans. In rats, Fkbp5 expression in the nucleus accumbens and ventral tegmental area, core regions of the reward system, was affected in a region-dependent manner and in opposite direction by maternal separation and alcohol drinking. Fkbp5 expression in the cingulate cortex was affected by the combined effect of maternal separation and alcohol drinking. In humans, the TT genotype, in the presence of a poor relationship between the child and parents, was associated with problematic drinking behavior. The present findings suggest that Fkbp5 expression in mesocorticolimbic dopaminergic regions associates with early life stress-mediated sensitivity to alcohol drinking and that FKBP5 genotype interacts with parent-child relationship to influence alcohol drinking. These findings are the first to point to a role of FKBP5 in propensity to alcohol misuse and call for studies of the underlying molecular mechanisms to identify potential drug targets.
authors.affiliation: Department of Pharmaceutical Bioscience, Uppsala University, Box 591, SE-75124, Uppsala, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Nylander
authors.affiliation: Department of Neuroscience, Uppsala University, Box 593, SE-75124, Uppsala, Sweden.
authors.forename: Aniruddha
authors.initials: A
authors.lastname: Todkar
authors.affiliation: Department of Pharmaceutical Bioscience, Uppsala University, Box 591, SE-75124, Uppsala, Sweden.
authors.forename: Linnea
authors.initials: L
authors.lastname: Granholm
authors.affiliation: Department of Neuroscience, Uppsala University, Box 593, SE-75124, Uppsala, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Vrettou
authors.affiliation: Department of Neuroscience, Uppsala University, Box 593, SE-75124, Uppsala, Sweden.
authors.forename: Megha
authors.initials: M
authors.lastname: Bendre
authors.affiliation: Department of Neuroscience, Uppsala University, Box 593, SE-75124, Uppsala, Sweden.
authors.forename: Wout
authors.initials: W
authors.lastname: Boon
authors.affiliation: School of Law, Psychology and Social Work, Örebro University, SE-70182, Örebro, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Andershed
authors.affiliation: School of Law, Psychology and Social Work, Örebro University, SE-70182, Örebro, Sweden.|Department of Psychology, University of Southern California, 3620 S. McClintock Ave, Los Angeles, CA, 90089-1061, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Tuvblad
authors.affiliation: Centre for Clinical Research, Västerås Central Hospital, SE-72189, Västerås, Sweden.
authors.forename: Kent W
authors.initials: KW
authors.lastname: Nilsson
authors.affiliation: Department of Neuroscience, Uppsala University, Box 593, SE-75124, Uppsala, Sweden. Erika.comasco@neuro.uu.se.
authors.forename: Erika
authors.identifier: http://orcid.org/0000-0002-2174-2068
authors.initials: E
authors.lastname: Comasco
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D000437:Alcoholism / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000523:psychology; D000818:Animals; D059647:Gene-Environment Interaction; D005838:Genotype; D006179:Gyrus Cinguli / Q000378:metabolism; D006801:Humans; D008297:Male; D008426:Maternal Deprivation; D009714:Nucleus Accumbens / Q000378:metabolism; D010287:Parent-Child Relations; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D012919:Social Behavior; D022021:Tacrolimus Binding Proteins / Q000235:genetics* / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000378:metabolism; D055815:Young Adult; D000099159:Tacrolimus Binding Protein 5
chemical_list: D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5
keywords: Alcohol; Brain; Expression; FKBP5; Genotype; Stress