Binge-like ethanol consumption increases corticosterone levels and neurodegneration whereas occupancy of type II glucocorticoid receptors with mifepristone is neuroprotective

Abstract

Excessive ethanol (EtOH) use leads to impaired memory and cognition. Using a rat model of binge-like intoxication, we tested whether elevated corticosterone (Cort) levels contribute to the neurotoxic consequences of EtOH exposure. Rats were adrenalectomized (Adx) and implanted with cholesterol pellets, or cholesterol pellets containing basal, medium or high Cort. Intragastric EtOH or an isocaloric control solution was given 3 times daily for 4 days to achieve blood alcohol levels (BALs) ranging between 200-350 mg/dl. Mean 24 hour (24-hr) plasma Cort levels were ~110 ng/ml and ~40 ng/ml in intact EtOH treated and intact control, respectively. Basal Cort replacement in EtOH-treated Adx animals animals did not exacerbate alcohol-induced neurodegeneration in the hippocampal dentate gyrus (DG) or the entorhinal cortex (EC) as observed by amino-cupric silver staining. In contrast, Cort replacement resulting in levels 2-fold higher (medium) than normal, or higher (high) in Adx-Cort-EtOH animals increased neurodegeneration. In separate experiments, pharmacological blockade of the Type II glucocortocoid (GC) receptor was initiated with mifepristone (RU38486; 0, 5, 15 mg/kg/day, i.p.). At the higher dose, mifepristone decreased the number of degenerating hippocampal DG cells in binge-EtOH treated intact animals, whereas, only a trend for reduction was observed in 15 mg/kg/day mifepristone treated animals in the EC, as determined by Fluoro Jade B staining. These results suggest that Cort in part mediates EtOH-induced neurotoxicity in the brain through activation of Type II GC receptors.

Neuroinflammation and Neurodegeneration in Adult Rat Brain from Binge Ethanol Exposure: Abrogation by Docosahexaenoic Acid

“…Cellular edema, a major and often intractable clinical problem that exacerbates neuropathology in brain ischemia and trauma, thus might elicit neuroinflammatory processes in binge ethanol abuse. A further contributor to the neurodamage in this binge model may well be stress-elevated circulating glucocorticoid (corticosterone), as recently reported [13]. (However, it is worth noting a paradox in that glucocorticoids have well-known edema-resolving effects, particularly under cerebral acidotic conditions [14]).…”

Acute oral administration of the novel, competitive and selective glucocorticoid receptor antagonist ORG 34517 reduces the severity of ethanol withdrawal and related hypothalamic–pituitary–adrenal axis activation

“…Rasmussen et al (2000) reported that free CORT was elevated in plasma during the early phases of withdrawal from continuous exposure to modest ethanol doses. Cippitelli et al (2014) demonstrate elevations in CORT plasma levels of over 100 ng/ml (i.e., 288 nM) in ethanol-dependent rats achieving BELs near 350 mg/dl. Sharrett-Field et al, (2013) demonstrated that CORT levels were elevated during withdrawal from a 4-day binge-ethanol regimen.…”

Binge-like ingestion of a combination of an energy drink and alcohol leads to cognitive deficits and motivational changes

“…This drinking pattern has been shown to produce cognitive deficits and motivational alterations following repeated alcohol exposure (Bechara et al, 2001;Harper and Matsumoto, 2005;Stephens and Duka, 2008;Sprow and Thiele, 2012;Cippitelli et al, 2014;Townshend et al, 2014). The combination of alcoholic beverages and energy drinks (EDs) has been suggested to favor binge drinking because of increased palatability (e.g., the sweet taste) and the common misconception that EDs antagonize the depressant effects of alcohol.…”