Targeting the Glucocorticoid Receptor Reduces Binge-Like Drinking in High Drinking in the Dark (HDID-1) Mice - PubMed (original) (raw)

. 2020 May;44(5):1025-1036.

doi: 10.1111/acer.14318. Epub 2020 Mar 27.

Affiliations

Targeting the Glucocorticoid Receptor Reduces Binge-Like Drinking in High Drinking in the Dark (HDID-1) Mice

Antonia M Savarese et al. Alcohol Clin Exp Res. 2020 May.

Abstract

Background: Chronic alcohol exposure can alter glucocorticoid receptor (GR) function in some brain areas that promotes escalated and compulsive-like alcohol intake. GR antagonism can prevent dependence-induced escalation in drinking, but very little is known about the role of GR in regulating high-risk nondependent alcohol intake. Here, we investigate the role of GR in regulating binge-like drinking and aversive responses to alcohol in the High Drinking in the Dark (HDID-1) mice, which have been selectively bred for high blood ethanol (EtOH) concentrations (BECs) in the Drinking in the Dark (DID) test, and in their founder line, the HS/NPT.

Methods: In separate experiments, male and female HDID-1 mice were administered one of several compounds that inhibited GR or its negative regulator, FKBP51 (mifepristone [12.5, 25, 50, 100 mg/kg], CORT113176 [20, 40, 80 mg/kg], and SAFit2 [10, 20, 40 mg/kg]) during a 2-day DID task. EtOH consumption and BECs were measured. EtOH conditioned taste and place aversion (CTA and CPA, respectively) were measured in separate HDID-1 mice after mifepristone administration to assess GR's role in regulating the conditioned aversive effects of EtOH. Lastly, HS/NPT mice were administered CORT113176 during DID to assess whether dissimilar effects from those of HDID-1 would be observed, which could suggest that selective breeding had altered sensitivity to the effects of GR antagonism on binge-like drinking.

Results: GR antagonism (with both mifepristone and CORT113176) selectively reduced binge-like EtOH intake and BECs in the HDID-1 mice, while inhibition of FKBP51 did not alter intake or BECs. In contrast, GR antagonism had no effect on EtOH intake or BECs in the HS/NPT mice. Although HDID-1 mice exhibit attenuated EtOH CTA, mifepristone administration did not enhance the aversive effects of EtOH in either a CTA or CPA task.

Conclusion: These data suggest that the selection process increased sensitivity to GR antagonism on EtOH intake in the HDID-1 mice, and support a role for the GR as a genetic risk factor for high-risk alcohol intake.

Keywords: Alcohol; Aversion; Binge Drinking; FKBP51; Glucocorticoid Receptor.

© 2020 by the Research Society on Alcoholism.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.. Mifepristone reduced binge-like ethanol intake and BECs in HDID-1 mice.

HDID-1 mice (n = 7–11/sex/dose) were tested in a 2-day ethanol DID, followed in subsequent weeks with water DID and saccharin DID. (a) The 50 mg/kg and 100 mg/kg doses of mifepristone significantly reduced ethanol intake (g/kg) in the 4-hour drinking session on Day 2, relative to vehicle. (b) The 50 mg/kg dose of mifepristone significantly reduced BECs relative to vehicle. In contrast, no dose of mifepristone reduced (c) water or (d) saccharin intake (ml/kg) relative to vehicle. BEC = blood ethanol concentration. Dotted line visually represents 0.8 mg/ml, the level of intoxication. All data collapsed on sex. (* = p < 0.05, *** = p < 0.001, **** = p < 0.0001)

Figure 2.

Figure 2.. CORT11376 reduced binge-like ethanol intake and BECs in HDID-1 mice.

HDID-1 mice (n = 12–13/sex/dose) were tested in a 2-day ethanol DID, followed in subsequent weeks with water DID and saccharin DID. (a) A sex by drug interaction revealed that males significantly reduced ethanol intake (g/kg) at the 40 mg/kg dose, while females significantly reduced ethanol intake at the 20 and 80 mg/kg doses, relative to vehicle during the 4-hour session on Day 2. (b) Each dose of CORT113176 reduced BECs relative to vehicle. There was no effect of CORT113176 on either (c) water or (d) saccharin intake (ml/kg) relative to vehicle. BEC = blood ethanol concentration. Dotted line visually represents 0.8 mg/ml, the level of intoxication. (* = p < 0.05, ** = p < 0.01, *** = p < 0.001)

Figure 3.

Figure 3.. SAFit2 did not reduce binge-like ethanol intake or BECs in HDID-1 mice.

HDID-1 mice (n = 12–13/sex/dose) were tested in a 2-day ethanol DID. SAFit2 administration did not reduce either (a) ethanol intake or (b) BECs. BEC = blood ethanol concentration. Dotted line visually represents 0.8 mg/ml, the level of intoxication. All data collapsed on sex.

Figure 4.

Figure 4.. HDID-1 mice exhibited a modest taste aversion to NaCl with a 2 g/kg dose of ethanol, but mifepristone did not enhance this aversive response.

HDID-1 mice (n = 11–12/dose/condition/drug) were tested in an ethanol conditioned taste aversion task to see whether mifepristone administration would enhance the aversive effects of ethanol. Pairing of a 2 g/kg ethanol injection with the NaCl tastant produced a conditioned taste aversion, as evidenced by a main effect of condition on Day 20 that did not exist at baseline (Day 10). However, mifepristone did not moderate this effect. Data are shown separated by dose groups for ease of viewing. (* = p < 0.05; significant main effect of condition [ethanol vs. saline])

Figure 5.

Figure 5.. Mifepristone did not enhance the aversive response to ethanol in HDID-1 mice in an ethanol conditioned place aversion task.

HDID-1 mice (n = 30–32/drug) did not condition a place aversion to a 2 g/kg dose of ethanol, and mifepristone (50 mg/kg) did no effect on behavior. Data collapsed on sex.

Figure 6.

Figure 6.. CORT113176 did not reduce either binge-like ethanol intake or BECs in the founder line, HS/NPT.

HS/NPT mice (10–13/sex/dose) were tested in a 2-day ethanol DID. CORT113176 administration did not reduce either (a) ethanol intake or (b) BECs. BEC = blood ethanol concentration. Dotted line visually represents 0.8 mg/ml, the level of intoxication. All data collapsed on sex.

References

    1. BALI U, PHILLIPS T, HUNT H & UNITT J 2016. FKBP5 mRNA Expression Is a Biomarker for GR Antagonism. J Clin Endocrinol Metab, 101, 4305–4312. - PubMed
    1. BARKLEY-LEVENSON AM, CUNNINGHAM CL, SMITASIN PJ & CRABBE JC 2015. Rewarding and aversive effects of ethanol in High Drinking in the Dark selectively bred mice. Addict Biol, 20, 80–90. - PMC - PubMed
    1. BINDER EB, SALYAKINA D, LICHTNER P, WOCHNIK GM, ISING M, PUTZ B, PAPIOL S, SEAMAN S, LUCAE S, KOHLI MA, NICKEL T, KUNZEL HE, FUCHS B, MAJER M, PFENNIG A, KERN N, BRUNNER J, MODELL S, BAGHAI T, DEIML T, ZILL P, BONDY B, RUPPRECHT R, MESSER T, KOHNLEIN O, DABITZ H, BRUCKL T, MULLER N, PFISTER H, LIEB R, MUELLER JC, LOHMUSSAAR E, STROM TM, BETTECKEN T, MEITINGER T, UHR M, REIN T, HOLSBOER F & MULLER-MYHSOK B 2004. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet, 36, 1319–25. - PubMed
    1. BLAINE SK & SINHA R 2017. Alcohol, stress, and glucocorticoids: From risk to dependence and relapse in alcohol use disorders. Neuropharmacology, 122, 136–147. - PMC - PubMed
    1. BOUCHERY EE, HARWOOD HJ, SACKS JJ, SIMON CJ & BREWER RD 2011. Economic costs of excessive alcohol consumption in the U.S., 2006. Am J Prev Med, 41, 516–24. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources