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.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-016-0157-z) contains supplementary material, which is available to authorized users.

Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism

“…The present study identified 129 genes (FDR < 0.05) that were differentially expressed in alcohol dependent subjects (Supplementary table 1). FKBP5, a well studied gene that is asoociated with alcohol use [28][29][30][31] , showed increased expression in the PFC of alcohol dependent subjects in our differential gene expression analysis (l 2 FC 0.27; P = 4.57 x 10 -7 ). Other studies have also shown that FKBP5 plays a role in alcohol drinking behaviors in rodents 28,29 and humans 32 .…”

The selective FKBP51 inhibitor SAFit2 reduces alcohol consumption and reinstatement of conditioned alcohol effects in mice

“…The FKBP51 antagonist, SAFit2, was synthetized as described previously . For intraperitoneal injections, SAFit2 was solubilized in vehicle consisting of 4% EtOH, 5% Tween80, and 5% PEG400 in 0.9% saline.…”

“…For intraperitoneal injections, SAFit2 was solubilized in vehicle consisting of 4% EtOH, 5% Tween80, and 5% PEG400 in 0.9% saline. SAFit2 and vehicle were administered 12 hours and 1 hour before testing as short and long latency effects on emotional behavior had been reported . The plasma half‐life of SAFit2 is 9.7 hours after intraperitoneal application in mice and robust high plasma levels are achieved during sub‐chronic dosing.…”

“…Recently, the first highly selective inhibitors of FKBP51, SAFit1, and SAFit2 (K dFKBP51 = 4‐6nM, selectivity to FKBP52 > 10 000×) were developed . In animal studies, the brain‐permeable SAFit2 reduced corticosterone secretion during circadian peak times and after a dexamethasone CRF suppression test.…”

“…In animal studies, the brain‐permeable SAFit2 reduced corticosterone secretion during circadian peak times and after a dexamethasone CRF suppression test. SAFit2 also showed antidepressant and anxiolytic effects in mice . Here we asked whether a direct inhibition of FKBP51 with SAFit2 may serve as a new pharmacological strategy to reduce alcohol consumption and conditioned alcohol effects in a mouse model.…”