Pharmacology Unit, School of Pharmacy, University of Camerino, 62032 Camerino, Italy.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Int J Mol Sci. 2021 Apr 17;22(8):4184. doi: 10.3390/ijms22084184.
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% (/) 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.
酒精成瘾是一种慢性复发性疾病，其特征是大量饮酒和戒断时出现负面情绪状态，这导致了过度饮酒和易复发。应激、下丘脑-垂体-肾上腺（HPA）轴的失调以及糖皮质激素受体（GR）功能的改变与从娱乐性饮酒向酒精使用障碍（AUD）的转变有关。在这里，我们使用雄性和雌性 Wistar 和 Marchigian Sardinian 酒精偏好（msP）大鼠研究了 GR 药理学拮抗剂对酒精自我给药（SA）的影响，这是一种遗传选择用于过度饮酒且对压力高度敏感的啮齿动物品系。动物被训练进行 10%（/）酒精自我给药。一旦达到稳定的酒精 SA 基线，我们测试了 GR 拮抗剂米非司酮（0.0、10、30 和 60mg/kg；ip）和 CORT113176（0.0、10、30 和 60mg/kg）对酒精 SA 的影响。为了评估这两种化合物的作用是否是特异性的，将这两种药物用于类似的蔗糖 SA 方案进行了测试。最后，测定了酒精 SA 前后基础血液皮质酮（CORT）水平。米非司酮的系统注射剂量依赖性地降低了雄性和雌性 Wistars 中的酒精 SA，但对 msPs 没有影响。CORT113176 的给药降低了雄性和雌性 Wistars 以及雌性 msPs 中的酒精 SA，但对雄性 msP 大鼠没有影响。在最高剂量下，米非司酮还降低了雄性 Wistars 和雌性 msPs 中的蔗糖 SA，这表明药物 60mg/kg 时会出现一些非特异性作用。同样，CORT113176 的最高剂量（60mg/kg）降低了雄性 Wistars 的蔗糖摄入量。CORT 水平分析表明，两种大鼠品系的雌性血液 CORT 水平均高于雄性。饮酒降低了雌性的 CORT，但不降低雄性的 CORT。总的来说，这些发现表明选择性阻断 GR 选择性地降低了酒精 SA，并且与异质 Wistars 相比，遗传选择的 msP 大鼠对这种药物处理的敏感性较低。此外，结果表明 GR 拮抗作用的反应存在性别差异，以及酒精调节 GR 传递的能力。
