Evaluation of mifepristone effects on alcohol-seeking and self-administration in baboons.

Holtyn, August F.; Weerts, Elise M.

doi:10.1037/pha0000246

Cited by 11 publications

(11 citation statements)

References 45 publications

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“…was not effective in reducing ethanol self-administration (Holtyn and Weerts, 2019). A greater decrease in average daily intake was observed during 56 mg/kg of MIFE for four days with average daily ethanol intake decreasing from 3.2 to 1.8 g/kg/day, or 57% of baseline.…”

Section: Downloaded Frommentioning

confidence: 78%

Mifepristone Decreases Chronic Voluntary Ethanol Consumption in Rhesus Macaques

Jiménez

Walter

Shnitko

et al. 2020

J Pharmacol Exp Ther

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The efficacy of short-term treatment with mifepristone (MIFE), a high-affinity, nonselective glucocorticoid receptor (GR) antagonist, to reduce ethanol drinking was tested in a rhesus macaque model. Stable individual daily ethanol intakes were established, ranging from 1.6 g/kg/day to 4.0 g/kg/day (n=9 monkeys). Following establishment of chronic ethanol intake, a MIFE dosing regimen that modeled a study of rodent drinking and human alcohol craving was evaluated. Three doses of MIFE (17, 30, and 56 mg/kg/day) were each administered for four consecutive days. Both 30 and 56 mg/kg decreased ethanol intake compared to baseline drinking levels without a change in water intake. 56 mg/kg/day of MIFE produced the largest reduction in ethanol selfadministration with the average intake at 57% of baseline intakes. Cortisol was elevated during MIFE dosing and a mediation analysis revealed that the effect on ethanol drinking was fully mediated through cortisol. During a forced abstinence phase, access to 1.5 g/kg ethanol resulted in relapse in all drinkers and was not altered by 56 mg/kg MIFE treatment. Overall, these results show that during active drinking MIFE is efficacious in reducing heavy alcohol intakes in a monkey model, an effect that was related to MIFE-induced increase in cortisol. However, MIFE treatment did not eliminate ethanol drinking. Further, cessation of MIFE treatment resulted in a rapid return to baseline intakes and MIFE was not effective in preventing a relapse during early abstinence.Significance: Mifepristone reliably decreases average daily ethanol self-administration in a non-human primate model. This effect was mediated by cortisol, was most effective during open-access conditions, and did not prevent or reduce relapse drinking.

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Section: Downloaded Frommentioning

confidence: 78%

Mifepristone Decreases Chronic Voluntary Ethanol Consumption in Rhesus Macaques

Jiménez

Walter

Shnitko

et al. 2020

J Pharmacol Exp Ther

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“…Furthermore, baboons are phylogenetically close to humans and have comparable alcohol absorption and metabolism [ 42 ]. Importantly, the validity of this baboon CSR model has been extensively demonstrated in previous studies testing clinically-relevant alcohol behaviors and pharmacotherapies for AUD, including medications approved in clinical practice for AUD [ 46 – 48 , 89 – 93 ]. Thus, this model bridges the gap between rodent and human data.…”

Section: Discussionmentioning

confidence: 91%

Gut microbiome and metabolome in a non-human primate model of chronic excessive alcohol drinking

et al. 2021

Self Cite

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A relationship between the gut microbiome and alcohol use disorder has been suggested. Excessive alcohol use produces changes in the fecal microbiome and metabolome in both rodents and humans. Yet, these changes can be observed only in a subgroup of the studied populations, and reversal does not always occur after abstinence. We aimed to analyze fecal microbial composition and function in a translationally relevant baboon model of chronic heavy drinking that also meets binge criteria (drinking too much, too fast, and too often), i.e., alcohol ~1 g/kg and blood alcohol levels (BALs) ≥ 0.08 g/dL in a 2-hour period, daily, for years. We compared three groups of male baboons (Papio anubis): L = Long-term alcohol drinking group (12.1 years); S = Short-term alcohol drinking group (2.7 years); and C = Control group, drinking a non-alcoholic reinforcer (Tang®) (8.2 years). Fecal collection took place during 3 days of Drinking (D), followed by a short period (3 days) of Abstinence (A). Fecal microbial alpha- and beta-diversity were significantly lower in L vs. S and C (p’s < 0.05). Members of the commensal families Lachnospiraceae and Prevotellaceae showed a relative decrease, whereas the opportunistic pathogen Streptococcus genus showed a relative increase in L vs. S and C (p’s < 0.05). Microbiota-related metabolites of aromatic amino acids, tricarboxylic acid cycle, and pentose increased in L vs. S and C (FDR-corrected p < 0.01), with the latter two suggesting high energy metabolism and enhanced glycolysis in the gut lumen in response to alcohol. Consistent with the long-term alcohol exposure, mucosal damage and oxidative stress markers (N-acetylated amino acids, 2-hydroxybutyrate, and metabolites of the methionine cycle) increased in L vs. S and C (FDR-corrected p < 0.01). Overall, S showed few differences vs. C, possibly due to the long-term, chronic alcohol exposure needed to alter the normal gut microbiota. In the three groups, the fecal microbiome barely differed between conditions D and A, whereas the metabolome shifted in the transition from condition D to A. In conclusion, changes in the fecal microbiome and metabolome occur after significant long-term excessive drinking and are only partially affected by acute forced abstinence from alcohol. These results provide novel information on the relationship between the fecal microbiome and metabolome in a controlled experimental setting and using a unique non-human primate model of chronic excessive alcohol drinking.

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“…Reduced ethanol-seeking in rodents [177,178] Mixed results in primates; reduced chronic voluntary alcohol use but did not prevent relapse [179,180] Reduced alcohol craving and consumption [178,181,182] Reduce drinking…”

Section: Repurposedmentioning

confidence: 99%

“…Mixed results in primates; reduced chronic voluntary alcohol use but did not prevent relapse [ 179 , 180 ]…”

Section: Pharmacological Treatments For Audmentioning

confidence: 99%

“…Preclinically, both systemic and central amygdala injections of mifepristone were shown to suppress yohimbine stress-induced reinstatement of alcohol seeking, indicating that the central amygdala plays an important role in mifepristone’s effects on ethanol-seeking [ 177 , 178 ]. Recent preclinical research in primates has shown mixed results, such that mifepristone was shown to decrease chronic voluntary alcohol consumption in rhesus macaques at doses of 30 and 56 mg/kg per day [ 179 ], but had no effect on alcohol-seeking or self-administration in baboons at slightly lower doses of 10–30 mg/kg per day [ 180 ]. Of note, in the former study, cessation of mifepristone treatment resulted in a rapid return to baseline intake levels, and mifepristone was not effective in preventing a relapse during early abstinence.…”

Section: Pharmacological Treatments For Audmentioning

confidence: 99%

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Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder

Burnette

Nieto

Grodin

et al. 2022

Drugs

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Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is unlikely that one single medication will be effective for all individuals with an AUD. As such, there is a need to develop new, more effective, and diverse pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. In this qualitative literature review, we discuss the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD with a clinical perspective. Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin, N-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Overall, many repurposed and novel agents discussed in this review demonstrate clinical effectiveness and promise for the future of AUD treatment. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD.

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Evaluation of mifepristone effects on alcohol-seeking and self-administration in baboons.

Cited by 11 publications

References 45 publications

Mifepristone Decreases Chronic Voluntary Ethanol Consumption in Rhesus Macaques

Mifepristone Decreases Chronic Voluntary Ethanol Consumption in Rhesus Macaques

Gut microbiome and metabolome in a non-human primate model of chronic excessive alcohol drinking

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder

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