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

Abstract

Background The development of ethanol dependence is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis and activation of type II glucocorticoid receptors (GR). These effects may contribute to withdrawal-associated anxiety, craving and relapse to drinking. The present studies examined acute and oral administration of the novel, selective and competitive GR antagonist ORG 34517 on the severity of ethanol withdrawal. Methods Adult, male Sprague-Dawley rats were administered ethanol (4g/kg/i.g.) twice daily for 5 days followed by 2 days of withdrawal for 1, 2 or 3 consecutive cycles. Blood ethanol levels (BELs) were determined at 0930 on Day 4 of each week, while blood corticosterone levels (BCLs) were obtained at 1100 hrs on the first day of each ethanol withdrawal. During early withdrawal, subjects received oral administration of ORG 345617 (60 mg/kg/i.g.) or a placebo and withdrawal was monitored. Results Peak BELs of 225.52 mg/dl were observed during the third week. Withdrawal from three cycles of the regimen produced marked behavioral abnormalities (e.g. aggression, rigidity, and hypoactivity) and significant increases in BCLs of ethanol-dependent subjects. Acute, oral administration of ORG 34517 during early withdrawal significantly reduced both the severity of ethanol withdrawal, as reflected in reduced rigidity, aggression, and hypoactivity, and elevations in BCL without producing any sedative-like effects. Conclusions The present findings demonstrate that repeated ethanol exposure and withdrawal is associated with significant behavioral abnormalities and dysregulation of HPA axis activation. Further these data suggest that selective GR antagonists should be further considered as putative pharmacotherapies for treatment of ethanol dependence.

Group 1 mGlu-family proteins promote neuroadaptation to ethanol and withdrawal-associated hippocampal damage

“…Given that nasogastric gavage administration of MPEP (10 mg/kg) for one month reduced Parkinsonian symptoms in non-human primates (Morin et al, 2013), we chose to deliver this compound to subjects orally suspended in either ethanol-containing or an isocaloric diet. Ethanol and control diets were composed of 30% v/v Vanilla Ensure® (Abbott Nutrition, Columbus Ohio) and an equal quantity of double-distilled water (after Sharrett-Field et al, 2013; Reynolds et al, 2015B). Ethanol-containing diets were composed of 40% v/v 200 proof ethanol (Sigma-Aldrich, San Diego, CA) whereas control diets were isocalorically matched to ethanol-containing diets via substitution of maltose (Sigma-Aldrich) so as to yield equivalent caloric intake.…”

“…Withdrawal behavior was monitored in a square Plexiglas chamber for two minutes. During this time, two experimenters, blinded to experimental conditions, rated physical effects of withdrawal using a modified behavioral scale that was described in detail previously in our laboratory (Reynolds et al, 2015B; Self et al, 2009) using a 10-point discrete scale (i.e., all or nothing). This scale measured the following behaviors: rigidity, tremor, stereotypy, retropulsion, dystonic gait, hypoactivity, aggression, splayed paws, vocalization, and seizure.…”

“…Samples were stored at −20°C until further analyses of BELs using a colormetric assay (Abcam [Cambridge, United Kingdom]) for Week 1 and the Analox for Weeks 2 and 3. Analox methodology is described in detail in a prior report (Reynolds et al, 2015B). For the ELISA assay, alcohol oxidase oxidized ethanol to generate hydrogen peroxide, which reacts with the probe included in the assay to generate color.…”

“…Further, the role of activated group 1 mGlu1-family proteins is not fully characterized with regards to ethanol withdrawal-induced neurotoxicity produced by multiple episodes of withdrawal. The present studies sought to examine the functional relationship between ethanol-associated activation of group 1 mGlu-family proteins and subsequent withdrawal-associated cytotoxicity and withdrawal abnormalities following exposure to chronic, intermittent ethanol (CIE) as previously reported using these models in vitro (after Reynolds et al, 2015A) and in vivo (after Reynolds et al, 2015B). …”

Corticosterone enhances N-methyl-d-aspartate receptor signaling to promote isolated ventral tegmental area activity in a reconstituted mesolimbic dopamine pathway

“…Numerous in vivo studies have demonstrated enhanced striatal dopamine and glutamate efflux in animals exposed to stressors and methamphetamine (Matuszewich and Yamamoto, 2004) and research has indicated that exposure to chronic CORT significantly enhanced methamphetamine-induced dopaminergic nerve terminal damage (Kelly et al, 2012). Others have demonstrated the importance of the GR in the development of ethanol dependence and subsequent ethanol withdrawal (Jacquot et al, 2008; Reynolds et al, 2015; Rotter et al, 2012; Sharrett-Field et al, 2013). Taken together, these findings demonstrate the ability of stress and the resulting rise in CORT levels to sensitize the reward pathway, and in particular the VTA, to future excitatory amino acid signaling such as that seen with psychostimulant and ethanol use.…”