Abstract

Alcoholism is a chronically relapsing disorder characterized by high alcohol intake and a negative emotional state during abstinence, which contributes to excessive drinking and susceptibility to relapse. Stress, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and alterations in glucocorticoid receptor (GR) function have been linked to transition from recreational consumption to alcohol use disorder (AUD). Here, we investigated the effect of pharmacological antagonisms of GR on alcohol self-administration (SA) using male and female Wistar and Marchigian Sardinian alcohol-preferring (msP) rats, a rodent line genetically selected for excessive alcohol drinking and highly sensitive to stress. Animals were trained to self-administer 10% (v/v) alcohol. Once a stable alcohol SA baseline was reached, we tested the effect of the GR antagonists mifepristone (0.0, 10, 30 and 60 mg/kg; i.p.) and CORT113176 (0.0, 10, 30 and 60 mg/kg) on alcohol SA. To evaluate whether the effects of the two compounds were specific for alcohol, the two drugs were tested on a similar saccharin SA regimen. Finally, basal blood corticosterone (CORT) levels before and after alcohol SA were determined. Systemic injection with mifepristone dose-dependently reduced alcohol SA in male and female Wistars but not in msPs. Administration of CORT113176 decreased alcohol SA in male and female Wistars as well as in female msPs but not in male msP rats. At the highest dose, mifepristone also reduced saccharin SA in male Wistars and female msPs, suggesting the occurrence of some nonspecific effects at 60 mg/kg of the drug. Similarly, the highest dose of CORT113176 (60 mg/kg) decreased saccharin intake in male Wistars. Analysis of CORT levels revealed that females of both rat lines had higher blood levels of CORT compared to males. Alcohol consumption reduced CORT in females but not in males. Overall, these findings indicate that selective blockade of GR selectively reduces alcohol SA, and genetically selected msP rats are less sensitive to this pharmacological manipulation compared to heterogeneous Wistars. Moreover, results suggest sex differences in response to GR antagonism and the ability of alcohol to regulate GR transmission.

Highlights

  • Alcohol use disorder (AUD) is a complex psychiatric condition characterized by excessive drug use, loss of control over its consumption and emergence of a negative emotional state during withdrawal that contribute to relapse [1]

  • We tested the effect of mifepristone on alcohol SA under Fixed Ratio 1 (FR1) schedule

  • The present study investigated the effect of glucocorticoid receptor antagonism on The present study investigated the effect of glucocorticoid receptor antagonism on alcohol drinking in genetically-selected Marchigian Sardinian alcohol-preferring (msP) rats in comparison with nonselected Wistar alcohol drinking in genetically-selected msP rats in comparison with nonselected Wistar rats

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Summary

Introduction

It is possible that their innate propensity to consume high amounts of alcohol is driven by the attempt to self-medicate from an innate negative affect, mimicking the subpopulation of humans with alcoholism that consume alcohol for tension relief purposes [14,15] Consistent with this view, earlier studies showed that msP rats carry two single nucleotide polymorphisms in the promoter region of the CRF1 receptor (CRF1-R). Systemic and intra-CeA administration of mifepristone, a nonselective glucocorticoid and progesterone receptor antagonist, reduced alcohol intake and yohimbine-induced reinstatement of alcohol seeking [27,28] It is unknown whether the constitutive alteration of GR levels of msP rats might contribute to their excessive alcohol-drinking phenotype. Several sex differences have been described in response to stress and to alcohol, and that the HPA axis function is greater in female rats, in the present study we tested males and females separately [15,29,30,31,32,33]

Results
Discussion
Animals
Self-Administration Apparatus
Self-Administration Training
Experiment 3
4.10. Statistical Analysis
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