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

Abstract

BackgroundChronic 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.MethodsIn 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.ResultsGR 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.ConclusionThese 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.

The Endocrine System and Alcohol Drinking in Females

“…Preliminary data in mice selectively bred for a high binge drinking phenotype determined that CORT113176 significantly decreased binge drinking in both male and female mice, and that female mice were more sensitive to the effect. 107 Pharmacological strategies targeting the CRF 1 receptor and glucocorticoid receptor systems may be differentially effective in males versus females, and new strategies targeting these systems could have greater specificity for females. 92 For example, inhibiting molecules that facilitate the transport of glucocorticoid receptors to their classical intracellular receptor might normalize high glucocorticoid levels in females.…”

“…Preliminary data in mice selectively bred for a high binge drinking phenotype determined that CORT113176 significantly decreased binge drinking in both male and female mice, and that female mice were more sensitive to the effect. 107 …”

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

“…Importantly, this model captures the complex, polygenic nature of aberrant drinking patterns. 23,40 Of the compounds tested, the only significant findings were that tacrolimus reduced ethanol intake and reduced BALs below the level of intoxication in both male and female HDID-1 mice at all 3 doses tested (0.5, 1, and 2 mg/kg). Previous work suggests that inhibiting calcineurin signaling may be an effective molecular means of reducing ethanol intake and preference.…”

“…Mice were singly housed 1 week prior to testing and pseudorandomized to dose group. DID testing was performed as previously described, 40 whereby water bottles were replaced with a single 10 ml tube (fitted with a metal sipper and a ball bearing) containing 20% ethanol 3 hours into the dark cycle. Meniscus levels were recorded at the beginning and end of the 2 or 4-hour drinking period.…”

“…Immediately after the 4-hour time point on Day 2, a 20 μl blood sample was taken from the peri-orbital sinus to determine BALs using gas chromatography. 40 Animals were then allowed 6 days to rest before they were re-randomized into dose groups and tested for water DID (tap water in 10 ml tubes). One week later, animals were re-randomized again and tested for saccharin DID (8.5 mM saccharin in tap water).…”