Effect of Glucocorticoid Receptor Antagonism on Alcohol Self-Administration in Genetically-Selected Marchigian Sardinian Alcohol-Preferring and Non-Preferring Wistar Rats - PubMed (original) (raw)

Effect of Glucocorticoid Receptor Antagonism on Alcohol Self-Administration in Genetically-Selected Marchigian Sardinian Alcohol-Preferring and Non-Preferring Wistar Rats

Federica Benvenuti et al. Int J Mol Sci. 2021.

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.

Keywords: alcohol preferring rats; alcohol self-administration; alcohol use disorder; glucocorticoids; mifepristone; stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Effect of mifepristone on alcohol and saccharin self-administration in male and female msP and Wistar rats. Male and female msP and Wistar rats were treated with mifepristone (0.0, 10, 30 and 60 mg/kg) i.p., 90 min prior to test session. (A) Mifepristone treatment significantly reduced the number of alcohol rewards in male and female Wistars. Drug treatment did not decrease alcohol SA in male and female msPs. (B) At the dose of 60 mg/kg, mifepristone significantly reduced saccharin SA in male Wistars and in female msPs. Data are expressed as the mean ± SEM of number of: (a) reinforced responses (rewards) at the active lever and (b) total responses at the inactive lever. Significant difference from vehicle (0.0 mg/kg): * p < 0.05; ** p < 0.01; *** p < 0.001.

Figure 2

Effect of CORT113176 on alcohol and saccharin self-administration in male and female msP and Wistar rats. Male and female msP and Wistar rats were treated with CORT113176 (0.0, 10, 30 and 60 mg/kg) i.p., 90 min prior to test session. (A) CORT113176 treatment significantly reduced the number of alcohol rewards in male and female Wistars and in female msP rats. (B) CORT113176 at the dose of 60 mg/kg significantly reduced saccharin SA in male Wistar rats only. Data are expressed as the mean ± SEM of number of: (a) reinforced responses at the active and (b) total responses at inactive lever. Significant difference from vehicle (0.0 mg/kg): ** p < 0.01; * p < 0.05.

Figure 3

Blood corticosterone (CORT) levels under basal conditions and after alcohol SA sessions in male and female msP and Wistar rats. Females displayed significantly higher blood CORT levels than males independently of rat strain. Female Wistars had higher CORT levels than female msPs. Alcohol consumption decreased basal CORT levels in female animals only. In both rat lines, CORT levels of male rats remained unchanged following alcohol SA. Data are presented as mean ± SEM. Main effect of sex: **** p < 0.0001; main effect of sex x alcohol condition: ### p < 0.001; $ p < 0.05 vs. msP same condition and sex (sex x strain interaction).

References

1. Koob G.F. Theoretical Frameworks and Mechanistic Aspects of Alcohol Addiction as a Reward Deficit Disorder. Curr. Top. Behav. Neurosci. 2013;13:3–30. - PMC - PubMed
1. Witkiewitz K., Litten R.Z., Leggio L. Advances in the Science and Treatment of Alcohol Use Disorder. Sci. Adv. 2019;5:eaax4043. doi: 10.1126/sciadv.aax4043. - DOI - PMC - PubMed
1. Stephens M.A.C., Wand G. Stress and the HPA Axis: Role of Glucocorticoids in Alcohol Dependence. Alcohol Res. 2012;34:468–483. - PMC - PubMed
1. Edwards S., Little H.J., Richardson H.N., Vendruscolo L.F. Divergent Regulation of Distinct Glucocorticoid Systems in Alcohol Dependence. Alcohol. 2015;49:811–816. doi: 10.1016/j.alcohol.2015.04.004. - DOI - PMC - PubMed
1. Herman J.P., Cullinan W.E. Neurocircuitry of Stress: Central Control of the Hypothalamo–Pituitary–Adrenocortical Axis. Trends Neurosci. 1997;20:78–84. doi: 10.1016/S0166-2236(96)10069-2. - DOI - PubMed

Effect of Glucocorticoid Receptor Antagonism on Alcohol Self-Administration in Genetically-Selected Marchigian Sardinian Alcohol-Preferring and Non-Preferring Wistar Rats - PubMed (original) (raw)