The Role of the GR and Individual Variation in Alcohol Use Disorder

Abstract

Alcohol use disorder (AUD), characterized by continued alcohol consumption despite negative consequences, affects millions of people worldwide while limited treatment options are available. Only a subset of regular alcohol users develops AUD, but the cause of this individual vulnerability is not fully understood. Stress systems have been implicated in AUD, but knowledge of the role of the stress-related glucocorticoid receptor (GR) in the development and maintenance of alcohol drinking in AUD is limited. Therefore, the aim of this study was to determine the role of the GR in AUD-like behaviours. To that aim, we performed two rat studies.

In the first, we determined the effects of a GR antagonist (CORT113176) on 3 key features of AUD, i.e. alcohol consumption, loss of control over alcohol use and motivation for alcohol, in Lister Hooded rats that drink low, medium or high levels of alcohol (LD, MD and HD, respectively). After 8 weeks of alcohol consumption on an intermittent alcohol access (IAA) schedule, 36 rats were divided into these subgroups based on level of alcohol consumption. Subsequently, they received injections with CORT113176 (60 mg/kg and/or 100 mg/kg) and vehicle before (1) home cage alcohol consumption on an IAA schedule, (2) consumption of alcohol, adulterated with quinine, to assess loss of control over alcohol use, and (3) operant alcohol self-administration using a progressive ratio schedule of reinforcement, to assess motivation for alcohol. GR antagonism by CORT113176 (60 mg/kg and 100 mg/kg) significantly decreased home cage alcohol intake. However, GR antagonism by CORT113176 (100 mg/kg) did not affect loss of control over alcohol nor motivation for alcohol.

In the second study, we compared individual variation in alcohol self-administration in two punishment models, to determine the optimal conditions for studying individual differences in loss of control over alcohol use. After two months of IAA alcohol consumption, subgroups of LD and HD rats were selected and trained to self-administer alcohol in an operant task. The rats were trained/tested in (i) a direct punishment model based on a fixed ratio-2 schedule of reinforcement, and (ii) our novel Seeking under Threat of Adversity (STA) model, which is based on a random interval seeking-taking chain schedule of reinforcement, involving probabilistic threat of adversity, i.e. footshock punishment. We found differences between the LD and HD, most pronounced in the STA experiment; HD showed greater levels of responding despite threat of adversity compared to LD.

Taken together, our findings confirm involvement of the GR in alcohol consumption, but not other AUD-like behaviours. Additionally, our findings suggest that drinker subtype is a good predictor for development of loss of control over alcohol use, suggest a greater degree of loss of control in HD, and provide further support for the STA model as a suitable model to study AUD-like behaviour. IAA and STA in Lister Hooded rats can therefore be used in future investigations of the underlying mechanisms that promote loss of control in addiction, the role of GR therein, and may ultimately contribute to the development of improved therapeutic strategies for addiction.