Targeting the glucocorticoid receptor reduces binge-like drinking in High Drinking in the Dark (HDID-1) mice.
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 non-dependent 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 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. Ethanol consumption and BECs were measured. Ethanol 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 ethanol. 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 ethanol 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 ethanol intake or BECs in the HS/NPT mice. Although HDID-1 mice exhibit attenuated ethanol CTA, mifepristone administration did not enhance the aversive effects of ethanol in either a CTA or CPA task.


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