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

Abstract

There is still no widely effective pharmacotherapy for alcohol addiction available in the clinic. FK506-binding protein 51 (FKBP51) is a negative regulator of the glucocorticoid receptor signaling pathway that regulates the stress-induced glucocorticoid feedback circuit. Here we asked whether selective inhibitors of FKBP51, exemplified by SAFit2, may serve as a new pharmacological strategy to reduce alcohol consumption and conditioned alcohol effects in a mouse model. We report that a relatively short treatment with SAFit2 (20 mg/kg, ip) reduces ongoing 16 vol% alcohol consumption when administered during free access to alcohol in a two-bottle freechoice test. SAFit2 was also able to reduce alcohol consumption when given during an abstinence period immediately before relapse. In contrast, SAFit2 did not affect alcohol consumption when given during a relapse period after repeated withdrawal from alcohol. SAFit2 (10 and 20 mg/kg, ip) showed no effects when used in an intermittent drinking schedule. When 20 vol% alcohol was only available every other day, SAFit2 had no effect on drinking, no matter whether given during a drinking episode or the day before. SAFit2 (2 and 20 mg/kg, ip) did not affect the expression of an alcohol-induced conditioned place preference (CPP). However, SAFit2 was able to inhibit alcohol-induced reinstatement of an extinguished CPP in a dose-dependent way. Altogether, these data may suggest pharmacological inhibition of FKBP51 as a viable strategy to reduce alcohol seeking and consumption.

Corticosterone Levels and Glucocorticoid Receptor Gene Expression in High Drinking in the Dark Mice and Their Heterogeneous Stock (HS/NPT) Founder Line

“…The failure of HDID-1 mice to exhibit this ethanol-induced increase in Fkbp5 expression, particularly when the same dose of ethanol produced a robust glucocorticoid response in these mice (in Experiment 1), might suggest a maladaptive response to ethanol in the HDID-1 mice which leads to prolonged activation of GR transcriptional activity (without elevations in FKBP51 to inhibit GR) and/or a shifting in transcriptional targets in these mice away from Fkbp5 , at least in the NAc. Interestingly, although administration of an FKBP51 ( Fkbp5 ) inhibitor, SAFit2, reduced alcohol consumption in a two-bottle choice test in mice ( Konig et al, 2020 ), the same inhibitor was ineffective at reducing alcohol intake in the HDID-1 mice in DID ( Savarese et al, 2020 ). Although two-bottle choice and DID drinking are distinct, and it is still unknown whether SAFit2 would reduce two-bottle choice alcohol intake in the HDID-1 mice, it may be that the lack of ethanol-induced Fkbp5 expression in the HDID-1 mice contributed to the failure of SAFit2 to reduce binge-like ethanol intake in these mice.…”

Impaired hypothalamic feedback dysregulates brain glucocorticoid signaling in genetically‐selected Marchigian Sardinian alcohol‐preferring rats

“…GR sensitivity to glucocorticoids, for instance, is moderated by co‐chaperone proteins (peptidylprolyl isomerase D and FK506 binding protein) that alter the nuclear translocation profile of this receptor 59 . In this regard, emerging studies are elucidating the role of these regulator proteins in the expression of stress‐ and alcohol‐induced phenotypes 60,61 …”

Structure-Based Design of High-Affinity Macrocyclic FKBP51 Inhibitors

“…The recent discovery of the first FKBP51-selective ligands (SAFit1 and SAFit2) provided powerful tools to study the role of FKBP51 in cellular and animal models. ,,,− A newly discovered transient binding pocket is the key to selectivity for FKBP51 over the highly homologous FKBP52. ,− Nevertheless, SAFit1 and SAFit2 are far from becoming drug candidates due to their high molecular weight and the associated poor physicochemical properties . Additionally, the binding site of FKBP51 is shallow and the creation of low molecular mass inhibitors with high ligand efficiency and sufficient potency is extremely challenging. ,− …”