Effects of Tacrolimus and Other Immune Targeting Compounds on Binge-Like Ethanol Drinking in High Drinking in the Dark Mice

Abstract

High Drinking in the Dark (HDID-1) mice represent a unique genetic risk model of binge-like drinking and a novel means of screening potential pharmacotherapies to treat alcohol use disorders (AUDs). We tested the effects of tacrolimus (0, 0.5, 1, and 2 mg/kg), sirolimus (0, 5, 10, and 20 mg/kg), palmitoylethanolamide (PEA; 0, 75, 150, and 225 mg/kg), and secukinumab (0, 5, 20, and 60 mg/kg) on binge-like ethanol intake (2-day, “Drinking in the Dark” [DID]) and blood alcohol levels (BALs) in HDID-1 mice. Tacrolimus reduced ethanol intake and BALs. Tacrolimus had no effect on water intake, but reduced saccharin intake. There was no effect of sirolimus, PEA, or secukinumab on ethanol intake or BALs. These results compare and contrast with previous work addressing these compounds or their targeted mechanisms of action on ethanol drinking, highlighting the importance of screening a wide range of models and genotypes to inform the role of neuroimmune signaling in AUDs.

Sex-dependent factors of alcohol and neuroimmune mechanisms

“…PDE4-D inhibitors transiently decreases alcohol drinking, while PDE4-B has no effect on drinking in either sex ( Blednov et al, 2023 ). Another report examined 4 different immune related compounds (tacrolimus, sirolimus, palmitoylethanolamide, [PEA] and secukinumab) in a HDID-1 drinking mice model in both males and females ( Grigsby et al, 2020 ). Out of the 4 immune-related drugs, tacrolimus reduced alcohol intake and BALs in both male and female HDID-1 mice across various doses ( Grigsby et al, 2020 ).…”

“…Another report examined 4 different immune related compounds (tacrolimus, sirolimus, palmitoylethanolamide, [PEA] and secukinumab) in a HDID-1 drinking mice model in both males and females ( Grigsby et al, 2020 ). Out of the 4 immune-related drugs, tacrolimus reduced alcohol intake and BALs in both male and female HDID-1 mice across various doses ( Grigsby et al, 2020 ). Sirolimus, PEA, and secukinumab showed no significant changes in alcohol drinking or unique sex differences in responding for alcohol in male and female HDID-1 mice ( Grigsby et al, 2020 ).…”

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

“…Because selective breeding principally changes the frequencies of genes affecting the targeted trait, any other differences between the selected line and its non-selected founder line may reflect coordinate genetic influences on the two traits. Thus, comparisons between HDID-1 and the founder HS/NPT lines have successfully been used to investigate the genetic and molecular determinants of high-risk drinking and identify potential pharmacotherapies for AUD ( Cozzoli et al, 2012 , 2016 ; Iancu et al, 2013 , 2018 ; Crabbe et al, 2017 , 2020 ; Ferguson et al, 2018 , 2019 ; Grigsby et al, 2020 ; Ozburn et al, 2020 ; Pozhidayeva et al, 2020 ; Robinson et al, 2020 ; Savarese et al, 2020 ). To test the effects of GR antagonism within this selectively bred line, HDID-1 mice were given both mifepristone, a non-selective steroid hormone receptor antagonist, and CORT113176, a specific GR antagonist.…”

Midazolam, methamphetamine, morphine and nicotine intake in high‐drinking‐in‐the‐dark mice

“…The high‐drinking‐in‐the‐dark (HDID) replicate lines of mice (HDID‐1 and HDID‐2) have been selectively bred to achieve high blood alcohol levels (BALs) in the drinking‐in‐the‐dark (DID) task 8 and now represent two unique genetic models of risk for binge‐like ethanol intake 9,10 . These mice have since been used as animal models to probe the genetic, molecular and neural underpinnings of AUD 11–18 and to screen potential pharmacotherapies for AUD 11,19–22 . However, little is known about the extent to which the HDID lines of mice consume other addictive drugs, which would provide information about shared genetic influences for risk of comorbid drug use.…”

“…9,10 These mice have since been used as animal models to probe the genetic, molecular and neural underpinnings of AUD [11][12][13][14][15][16][17][18] and to screen potential pharmacotherapies for AUD. 11,[19][20][21][22] However, little is known about the extent to which the HDID lines of mice consume other addictive drugs, which would provide information about shared genetic influences for risk of comorbid drug use.…”