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. Author manuscript; available in PMC: 2020 Jun 1.
Published in final edited form as: Exp Clin Psychopharmacol. 2018 Dec 20;27(3):227–235. doi: 10.1037/pha0000246

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

August F Holtyn a, Elise M Weerts b
PMCID: PMC6727199  NIHMSID: NIHMS1048342  PMID: 30570274

Abstract

Mifepristone, a type II glucocorticoid receptor antagonist, is under investigation as a potential pharmacotherapy for alcohol use disorder. This study examined effects of chronic administration of mifepristone on alcohol seeking and self-administration in large nonhuman primates. Adult baboons (n=5) self-administered alcohol 7 days/week under a chained schedule of reinforcement (CSR). The CSR was comprised of three components in which distinct cues were paired with different schedule requirements, with alcohol available for self-administration only in the final component, to model different phases of alcohol anticipation, seeking, and consumption. Under baseline conditions, baboons self-administered an average of 1 g/kg/day of alcohol in the self-administration period. Mifepristone (10, 20, and 30 mg/kg) or vehicle was administered orally 30 minutes before each CSR session for 7 consecutive days. In a separate group of baboons (n=5) acute doses of mifepristone (10, 20, and 30 mg/kg) were administered, and blood samples were collected over 72 hours to examine mifepristone pharmacokinetics. Some samples also were collected from the baboons that self-administered alcoh6ol under the CSR after the chronic mifepristone condition. Mifepristone did not alter alcohol seeking or self-administration under the CSR when compared to the vehicle condition. Mifepristone pharmacokinetics were nonlinear, and appear to be capacity limited. In sum, mifepristone did not reduce alcohol-maintained behaviors when administered to baboons drinking 1 g/kg daily.

Keywords: mifepristone, alcohol, seeking, self-administration, baboons

Mifepristone, a glucocorticoid receptor antagonist that binds with high affinity at type II glucocorticoid receptors, is under investigation as a potential pharmacotherapy for alcohol use disorder. Both preclinical and clinical studies provide evidence of the potential of mifepristone for alcohol use disorder treatment. In rats exposed to chronic intermittent alcohol vapor, mifepristone blocked development of physical dependence, prevented escalation of voluntary alcohol intake over time, and prevented persistent alcohol seeking responses during abstinence (Vendruscolo et al., 2012). Likewise, mifepristone has been shown to reduce the severity of alcohol withdrawal symptoms (Sharrett-Field, Butler, Berry, Reynolds, & Prendergast, 2013), and prevent alcohol-withdrawal induced hyper-excitability and memory deficits in rodent models (Jacquot et al., 2008). Mifepristone has anxiolytic effects in various animal models of stress-induced anxiety (Jakovcevski, Schachner, & Morellini, 2011; Korte, De Boer, De Kloet, & Bohus, 1995), and suppresses yohimbine-induced (i.e., stress induced) reinstatement of alcohol seeking when administered into the central amygdala (Simms, Haass-Koffler, Bito-Onon, & Bartlett, 2012). In humans, daily dosing with 600 mg mifepristone for 7 days reduced alcohol cue-induced craving and self-reported number of drinks per week in a randomized placebo-controlled trial with 56 non-treatment seeking alcohol-dependent adults (Vendruscolo et al., 2015).

Reviews on the use of animal models in the development of medications for alcohol use disorder have highlighted the importance of continuing to evaluate medications that reach clinical trials. These types of evaluations may serve to further validate animal models, optimize therapeutic doses and dosing conditions, and to improve our understanding of treatment effects on behavioral processes that are associated with alcohol use disorder (Egli, 2005; Grant & Bennett, 2003; Ripley & Stephens, 2011). The present study examined effects of chronic administration of mifepristone on responding that produces access to alcohol and alcohol consumption in large nonhuman primates (baboons). Drug metabolism and pharmacokinetic parameters in baboons are more similar to humans than rodents (Jolivette & Ward, 2005; Ward & Smith, 2004), which may yield information on potential drug interactions with alcohol that may not be apparent in rodent models.

The model employed in the present study is based on incentive-motivational theories of drug addiction, which propose that Pavlovian conditioning and incentive learning may be primary factors in the maintenance of drug-taking behavior and the propensity to relapse after abstinence (Markou et al., 1993; Robinson & Berridge, 1993). Our Chained Schedule of Reinforcement (CSR) model extends on a rodent model based on these principles (Samson et al., 1998), in which the appetitive (seeking) and consummatory (self-administration) phases of alcohol drinking are assessed separately within the same experimental session. Like Samson’s procedure, our CSR procedure includes distinct phases of seeking and consumption, and adds a third “anticipatory” component. Each component occurs in the context of environmental cues and behavioral contingencies; alcohol or vehicle (water) is available for self-administration in the final component of the chain. In our initial studies in alcohol-drinking baboons (Weerts et al., 2006), a sequence of neutral cues was presented alone with no programmed contingencies in effect, and did not maintain operant responding. Following repeated presentation of the same cues paired with the three linked components consisting of different behavioral contingencies leading to alcohol access, orient and approach behaviors emerged and operant responses occurred during the three components.

In the present study, we utilized a group of baboons with extensive histories of self-administration of alcohol in the CSR to assess mifepristone effects on alcohol seeking and consumption. Previously, we have shown that these baboons consume physiologically relevant amounts of alcohol (~1 g/kg/day), 7-days a week, and resulting blood alcohol levels exceed 0.08% after the 2-hr self-administration period in the CSR (Holtyn, Kaminski, Wand, & Weerts, 2014; Kaminski et al., 2008). The baboons defend and maintain daily intake levels despite increasing response costs to gain access to the day’s supply of alcohol, and alcohol maintains higher breaking points than its vehicle (Kaminski et al., 2008). We have also demonstrated that seeking and self-administration behaviors associated with alcohol were augmented after abstinence (Weerts et al., 2006), and alcohol-maintained behaviors were more resistant to extinction when compared to behaviors maintained by a preferred, nonalcoholic beverage (Holtyn et al., 2014). In addition, alcohol seeking and self-administration were reduced by administration of naltrexone, baclofen, and varenicline (Duke, Kaminski, & Weerts, 2014; Holtyn, Kaminski, & Weerts, 2017; Kaminski, Duke, & Weerts, 2012; Kaminski & Weerts, 2014).

Method

Experiment 1: Effects of Chronic Mifepristone During Ongoing Alcohol Access

Subjects.

Five adult (15 to 18 years) male baboons (Papio anubis), initially weighing 24.6 to 35.9 kg, were individually housed in custom-designed primate cages that also served as the experimental chambers. All of the baboons (B6-B10) had histories of chronic alcohol self-administration under the CSR paradigm (1 baboon had 3 years, and 4 baboons had 13 to 15 years of alcohol self-administration). The baboons were fed standard primate biscuits, 2 pieces of fresh fruit or vegetables (70–120 g each), and a children’s chewable multivitamin daily. Body weight (kg) was determined during monthly medical exams. Weight restrictions/food deprivation were not a part of the current protocol, but food was controlled by delivery of weighed daily rations of standard primate biscuits all at once at the same time each day. The amount was sufficient for all food to be consumed daily and to maintain normal weights. Water was available ad libitum, except during sessions. The housing room was maintained under a 12-hour light/dark cycle, with lights on from 6:00 AM to 6:00 PM daily. The facilities were maintained in accordance with USDA and AAALAC standards. The protocol was approved by the Johns Hopkins University Animal Care and Use Committee and followed the Guide for the Care and Use of Laboratory Animals (2011).

Apparatus.

The experimental chambers were equipped with a bench along one side of the chamber and an aluminum intelligence panel mounted on the same side as the bench. The intelligence panel contained two response levers (Med Associates, Georgia, VT), two different colored jewel lights mounted above each lever, and a drinkometer (Kandota Instruments, Sauk Center, MN) with two white and two green lights that surrounded a protruding drink spout. All solutions were delivered from a 1000 ml bottle positioned above the chamber and connected to the drinkometer. A separate panel on the back wall contained three cue lights colored red, yellow, and blue. A speaker was mounted above the chambers for presentation of auditory tones. Experimental events were controlled remotely using Med Associates (East Fairfield, VT) software and hardware interfaced with a personal computer.

Chained Schedule of Reinforcement (CSR) Procedure.

As shown in Figure 1, the CSR includes three components, each of which is associated with distinct cues and different behavioral (schedule) requirements. Fulfilling the schedule requirement in each successive component is necessary to progress to the next component, and to gain access to the daily supply of alcohol. Alcohol is available only in the third and final component of the CSR. The full description of the CSR procedure has been described in detail previously (Kaminski et al., 2008; Weerts et al., 2006). Briefly, the CSR sessions were conducted seven days per week and began at the same time (8:30 AM) each day. The start of a session and Component 1 was signaled by a 3-s tone. During Component 1, a red cue light was illuminated for 20 min and all instrumental responses were recorded but had no programmed consequence. Component 1 ended after 20 min. Component 2 was signaled by the illumination of a yellow cue light and consisted of two links. During the first link, the jewel light over the left lever was continuously illuminated and a concurrent fixed-interval (FI) 10-min, fixed-time (FT) 20-min schedule was in effect on the left lever. That is, transition to the second link occurred a) with the first response on the left lever after 10 min elapsed or b) automatically after 20 min, whichever occurred first. During the second link, the jewel light over the left lever flashed and a fixed-ratio (FR) 10 schedule with a 90-min limited hold was in effect on the left lever. Completion of the FR10 resulted in transition to Component 3. If the FR was not completed within 90 min the session ended with no alcohol access for the day. During Component 3, the blue cue light and the jewel light over the right lever were illuminated, and the opportunity to orally self-administer drinks of alcohol was available according to an FR 5 schedule on the right lever followed by contact with the drinkometer spout. Completion of the FR 5 resulted in activation of the drinkometer and the blue jewel light turned off. Drinkometer activation was signaled by illumination of the white lights surrounded a protruding drink spout, and contact with the drink spout was signaled by illumination of the green lights surrounding the spout for the duration of contact. Alcohol was delivered for the duration of spout contact or for five seconds (~25–35 ml), whichever came first. This defined a single drink. After contact with the drink spout ended, the drinkometer lights turned off, and the blue jewel light over the right lever illuminated and the FR schedule was in effect for the next drink of alcohol. Component 3 ended after 120 min.

Figure 1.

Figure 1.

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Session timeline of the stimulus events and behavioral (schedule) requirements in effect under the three-component chained schedule of reinforcement (CSR). FI = Fixed Interval, FT = Fixed Time, and FR = Fixed Ratio.

Drugs.

Ethyl alcohol (190 Proof; Pharmco-AAPER, Brookville, CT, USA) was diluted with reverse osmosis purified drinking water to a concentration of 4% w/v alcohol (5% v/v). A concentration of 4% w/v alcohol was selected because it maintains higher rates of operant self-administration than high concentrations (e.g., 8–16% w/v), and is preferred over water by baboons with alcohol drinking experience when both are available concurrently (Ator & Griffiths, 1992). We previously demonstrated intake of ~1g/kg/day resulted in relevant blood alcohol levels (i.e., 80 mg/dL or 0.08%) in these baboons. Mifepristone (C-1073, Corcept Therapeutics Inc., Menlo Park, California) was administered orally. The oral route was selected because mifepristone is taken orally in human laboratory studies and clinical trials. The doses of mifepristone (10, 20, and 30 mg/kg) were selected based on similar total mifepristone doses used in some clinical trials (e.g., 300, 600, 900 mg) in alcohol drinkers and neuropsychological disorders (Blasey, Block, Belanoff, & Roe, 2011; Vendruscolo et al., 2015). Doses of 10 and 20 mg/kg were mixed in a sweet solution (100 ml Kool-Aid) and delivered via a syringe connected to a drink spout. Due to solubility issues, the highest mifepristone dose (30 mg/kg) was mixed in 1 tablespoon of peanut butter. The unadulterated Kool-Aid solution or plain peanut butter was administered orally using the same volume for control conditions. Consumption of doses was verified via observation.

Mifepristone Treatment During Alcohol Access.

After alcohol self-administration was stable (i.e., ± 20% volume of alcohol consumed) for three consecutive sessions, mifepristone (10, 20, and 30 mg/kg) or vehicle was administered for 7 consecutive days. Drug doses and vehicle were administered orally 30 minutes before each session and were given in mixed order across baboons. The stability criteria were always met before drug or vehicle was administered, and a washout period of at least 3 weeks preceded each dosing period.

Daily Observations.

Prior to initiation of the study, observers memorized a list of behavioral definitions, and training observations were conducted by pairs of observers. Daily 10-min behavioral observations were completed using a behavioral checklist and behavioral sampling technique. A trained observer sat in front of the baboon’s cage and recorded the occurrence (coded as a 1) and non-occurrence (coded as a 0) of the behaviors and postures as defined previously (Weerts, Ator, Grech, & Griffiths, 1998). Behaviors included aggression, ataxia, bruxism, jerks/tremors, lip droop, locomotion, slow movements, nose rub, scratch/groom, vomit/retch, wet dog shakes, and yawn. The postures were normal, head-below-torso, lying down, resting, withdrawn, and rigidly braced. Observations were completed after the administration of drug or vehicle. Daily intake of food (g) and water (ml) was recorded at the same time each day to allow for detection of changes in intake. Any biscuits not consumed in the past 24 hrs was coded as reduced food intake on the observation sheet (1=food remaining). These procedures have been used previously to evaluate effects of acute and chronic drug administration, and have been demonstrated to be sensitive to a wide range of drug effects (Goodwin et al., 2006, 2009; Holtyn et al., 2017; Weerts, Ator, Kaminski, & Griffiths, 2005; Weerts et al., 2005). Prior to the study, inter-observer reliability was calculated for pairs of observers. First, the occurrence or nonoccurrence of each behavior and posture recorded during each 1-min interval of the observation was counted for each observer. Then, the total agreements for occurrence of each behavior and posture and total agreements for the nonoccurrence of each behavior and posture was divided by the total number of intervals. Reliability was 95% or greater.

Data Analysis.

The primary variables of interest included measures of alcohol seeking (latency to respond on the left lever and total number of left lever responses in Link 1 and the rate of responding in Link 2 in Component 2) and measures of consumption (number of right lever responses, number of drinks, and total g/kg alcohol intake in Component 3). Total g/kg alcohol intake was calculated based on individual body weights and the total volume of alcohol consumed. For each baboon, the mean of the three sessions before each dosing period was used as the baseline for comparison with vehicle and drug doses; baseline levels of responding were similar across time for individual baboons. The mean of the seven sessions during each dosing period was used for vehicle and drug conditions for individual baboons; data were aggregated because values were similar across the seven sessions for individual baboons. Grand mean data were analyzed using repeated measures analysis of variance (ANOVA) with condition (baseline, vehicle, 10–30 mg/kg mifepristone) as a repeated measure. For all statistical analyses, a p-value of .05 or less was considered significant.

Experiment 2: Pharmacokinetic (PK) Evaluation

Subjects and Apparatus.

A separate group of adult (15 to 17 years) male baboons (n=5), initially weighing 24.2 to 30.9 kg, were used for a PK analysis of blood levels of mifepristone. All of the baboons (B1-B5) had histories of self-administration of a preferred, non-alcoholic beverage under the CSR (between 2 and 10 years). Acute doses of mifepristone (10, 20, and 30 mg/kg) were administered orally as in Experiment 1. Blood sampling was completed in baboons in which consumption of the full dose was verified; each dose was examined in 2 (20 mg/kg) or 3 (10 and 30 mg/kg) baboons. Mifepristone levels were also measured in four of the alcohol-drinking baboons (B6, B7, B8, B9) during chronic mifepristone. The procedures for feeding and housing the baboons were identical to those described in Experiment 1.

Blood Sampling Procedures.

The baboons were lightly anesthetized with ketamine and then 5 ml of blood was drawn using vacutainers with a K2EDTA tube. Blood samples were collected at 0.5, 1, 2, 4, 8, 24, 48, and 72 hours after acute administration of mifepristone. In the alcohol-drinking baboons, blood samples were collected at 1 hour (for the 30 mg/kg dose only) or 24 hours after the last dose of chronically administered mifepristone. Blood sampling was completed after the 7-day dosing period in which alcohol was available for self-administration. Upon completion of that phase, a sample was collected 24-hrs after dosing. For the 1-hr sample, an additional dose was administered and blood sampling was completed. Alcohol sessions were not in effect on days in which samples were collected. These time points for sampling were selected based on the drug’s half-life (approximately 25–30 hours) and to avoid interference with data collection during the alcohol drinking sessions. Samples were immediately centrifuged at 3200 rpm for 12 min, and then plasma was drawn off, transferred to two separate polypropylene tubes, and frozen until shipping for analysis. All samples were shipped overnight on dry ice and were analyzed by MicroConstants, Inc. (San Diego, CA).

Results

Experiment 1

During baseline sessions, the grand mean (+ SEM) alcohol intake was 692.4 (60.9) ml and 0.98 (0.04) g/kg, comparable to intake which has previously been reported to produce blood alcohol levels of >0.08% in these baboons (Holtyn et al., 2014; Kaminski et al., 2008). Figures 2 and 3 show effects of chronic administration of mifepristone on alcohol seeking and consumption, respectively. Chronic administration of mifepristone produced dose-related increases in the mean response latency in Component 2, but this did not reach statistical significance. Mifepristone also did not significantly change any other measures of alcohol-directed responding in any of the components and did not significantly alter alcohol consumption in the group, although, there was some individual variability. Each dose was associated with some decreases in behavior in at least one of the baboons (supplemental Table 1S); however, these were generally accompanied by decreases in food intake or vomiting and did not appear dose dependent (see below).

Figure 2.

Figure 2.

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Effects of chronic (7 day) administration of vehicle (V) or mifepristone (10–30 mg/kg) on alcohol seeking in Component 2 under the chained schedule of reinforcement for baboons (B6-B10). Data shown are group means (+ SEM) for response latency (a) and number of lever responses (b) during the FI schedule, and response rate (c) during the FR schedule of Component 2 from the 7 consecutive days of vehicle or mifepristone administration.

Figure 3.

Figure 3.

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Effects of chronic (7 day) administration of vehicle (V) or mifepristone (10–30 mg/kg) on alcohol self-administration and consumption in Component 3 under the chained schedule of reinforcement for baboons (B6-B10). Data shown are group means (+ SEM) for number of right lever responses (a), total number of drinks (b), and g/kg alcohol intake (c) during the 7 consecutive days of vehicle or mifepristone administration.

Behavioral observations conducted by laboratory personnel included the recording of common behavioral signs of drug side effects, as in our prior studies characterizing behavioral drug effects (Goodwin et al., 2006, 2009; Holtyn et al., 2017; Weerts, Ator, Kaminski, & Griffiths, 2005; Weerts et al., 2005). In Table 1, we show the number of baboons showing behavioral signs commonly observed as drug side effects in alcohol clinical trials such as increases in lethargy or sedation (increases in lying down and withdrawn postures), nausea/gastrointestinal symptoms (vomiting and retching), suppressed appetite/food intake, or augmentation of incoordination (ataxia). Administration of doses up to and including 30 mg/kg mifepristone were safe and produced minimal adverse effects, although vomiting was observed in one baboon (B9) following administration of the 30 mg/kg dose, and two baboons (B9 and B10) did not consume some of their biscuits (250 g) at the 20 and 30 mg/kg doses. None of the other observed behaviors showed significant changes (data not shown). Under baseline and during vehicle test days, all baboons consumed the entire food ration. Behaviors such as vomiting are not typically observed under baseline or vehicle conditions, so any incidence is considered significant.

Table 1.

Baboons (N=5; B6-B10) showing adverse behavioral effects after administration of vehicle (VEH) or mifepristone (10–30 mg/kg).

Mifepristone Dose
VEH 10 mg/kg 20 mg/kg 30 mg/kg
Decreased food intakea -- -- B9, B10 B9, B10
Vomit/retchb -- -- -- B9
Lying downc B8, B10 B10 B7, B10 B10
Withdrawnd -- -- -- --
Ataxiae -- -- -- --
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a

Any decrease in the amount of food consumed, including leaving part or all of the daily food ration.

b

Making an effort to vomit (often accompanied by a “gagging sound”) or disgorging the stomach contents through the mouth; may not expel the vomitus; in such cases, the presence of vomit may often be assumed if the animal subsequently engages in chewing and swallowing.

c

Lying down on either the bench or cage floor, appears lethargic, and is unresponsive to normal verbal or physical stimuli.

d

Sitting on either the floor or bench with chin on chest and unresponsive to normal stimuli.

e

Incoordination that is characterized by slow, uncertain movements and tremor; can also include swaying or falling over during sitting and locomotion.

Experiment 2

Table 2 shows plasma levels of mifepristone following acute (A) and chronic (B) administration of mifepristone. For acute mifepristone dosing, significant plasma levels of mifepristone were detected within 30 minutes of dosing in all baboons, and reached peak concentrations between 24–48 hours after dosing in the majority of baboons tested, although one baboon had high mifepristone levels between 30 minutes and 4 hours for the 10 mg/kg mifepristone dose. The highest plasma levels obtained at each dose ranged from 505–779 ng/ml (10 mg/kg), 263–583 ng/ml (20 mg/kg), and 484–831 ng/ml (30 mg/kg). Significant levels of mifepristone were also detected at the 72-hour time point across all doses. For chronic mifepristone dosing, plasma levels ranged from 93.5–1490 ng/ml 1 hour after the last dose administration of 30 mg/kg mifepristone. This was included to provide assessment of accumulation effects from the daily dosing regimen. For samples collected 24 hours after the last chronic mifepristone dose, there was substantial individual variation. Plasma levels of mifepristone ranged from Below the Quantifiable Limit (BQL < 1.00 ng/ml) to 443 ng/ml (10 mg/kg dose), from 11.7–448 ng/ml (20 mg/kg dose), and from 1–128 ng/ml (30 mg/kg dose). This was substantially different than plasma levels of mifepristone (256–831 ng/ml) detected 24-hrs after acute administration of the 30 mg/kg determined in the non-alcohol drinking baboons (Table 2A).

Table 2A.

Mifepristone plasma levels (ng/ml) following acute administration of mifepristone in each baboon (B1-B5).

10 mg/kg Mifepristone
Time (hrs) post administration B1 B2 B3 Mean
0.5 165 365 779 436.3
1 182 295 690 389
2 208 387 635 410
4 172 366 762 433.3
8 77 372 536 328.3
24 195 638 328 387
48 505 609 200 438
72 182 313 46.9 180.6
20 mg/kg Mifepristone
Time (hrs) post administration B1 B4 Mean
0.5 14.9 65.1 -- 40
1 27.2 98.4 -- 62.8
2 38.6 97.1 -- 67.9
4 41.1 87.4 -- 64.3
8 59.3 88.6 -- 74
24 354 229 -- 291.5
48 583 263 -- 423
72 384 119 -- 251.5
30 mg/kg Mifepristone
Time (hrs) post administration B5 B3 B4 Mean
0.5 127 147 24 99.3
1 98.2 139 33.9 90.4
2 171 156 35.1 120.7
4 235 738 35.3 336.1
8 273 748 61 360.7
24 484 831 256 523.7
48 447 466 568 493.7
72 365 27.8 324 238.9
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Discussion

The present study examined effects of chronic administration of mifepristone, a glucocorticoid receptor antagonist, on alcohol seeking and self-administration in baboons. Using similar dosing parameters as those in human clinical trials, baboons were administered 10, 20, and 30 mg/kg mifepristone for 7 consecutive days. Mifepristone did not significantly alter alcohol-directed behaviors (anticipatory responses, seeking, or self-administration) during ongoing alcohol access in baboons drinking 1 g/kg alcohol daily. Prior preclinical studies in rodents have shown that mifepristone (20, 30, and 60 mg/kg i.p.; 40 mg/kg s.c.) reduced alcohol intake, blocked ethanol-induced conditioned place preference, and attenuated alcohol withdrawal symptoms (Koenig & Olive, 2004; Rotter et al., 2012; Sharrett-Field et al., 2013; Vendruscolo et al., 2015). There is one study in non-treatment seeking alcohol-dependent adults who received either oral mifepristone (600 mg/day) or placebo for 7 days, and alcohol abstinence was required during the last 3 days of the 7-day dosing period (Vendruscolo et al., 2015). Mifepristone reduced alcohol cue-induced craving during acute abstinence, and at the 2-week follow-up post treatment, participants randomized to mifepristone reported drinking less. Potentially relevant variables underlying differences in mifepristone effects on behaviors in our study and prior studies examining mifepristone effects on alcohol-related behaviors are discussed in detail below.

One important factor that is relevant to the current study is efficacy of mifepristone may be influenced by individual differences in pharmacokinetics, and the circulating levels of mifepristone obtained. In three randomized clinical trials of 7-day mifepristone treatment (300, 600, or 1200 mg) for adults with psychotic depression, change in psychotic symptoms was significantly and directly related to drug plasma concentrations (Blasey, DeBattista, Roe, Block, & Belanoff, 2009; Blasey, Block, Belanoff, & Roe, 2011; Blasey, McLain, & Belanoff, 2013; Block et al., 2017). While the overall effect of the trial was negative, a secondary analysis suggested therapeutic effects of mifepristone (i.e., a 50% reduction in psychotic symptoms) were only observed when trough plasma levels of participants were 1660 ng/ml or greater (Blasey et al., 2011). In the current study, the highest plasma level observed following chronic dosing with 30 mg/kg mifepristone was 1490 ng/ml 1-hr after last dose of the chronic dosing regimen. In addition, administration of higher doses did not result in substantially higher levels in plasma than the lower doses tested. This suggests that mifepristone metabolism may be capacity limited, which is consistent with some PK studies of orally administered mifepristone in humans. Following ingestion of a low dose of mifepristone (~1–50 mg), mifepristone levels have been shown to rise according to the dose. In contrast, following ingestion of higher doses (~100–800 mg), mifepristone levels have been observed to be similar at 24 hours after ingestion despite the administration of different doses; this plateau effect is also observed when relatively high doses of mifepristone are administered repeatedly (Heikinheimo, Kekkonen, & Lähteenmäki, 2003; Sarkar, 2002).

It is also possible that alcohol consumption may interfere with mifepristone bioavailablity. The cytochrome P450 3A4 enzyme (CYP3A4) is a major isozyme in the human liver and is known to metabolize a large variety of medications. The major form of cytochrome P450 in the baboon (P450 FA) is closely similar with human CYP3A4 isozymes (Dalet-Beluche, Boulenc, Fabre, Maurel, & Bonfils, 1992). CYP3A4 is the major enzyme responsible for the metabolism of mifepristone in humans (Jang, Wrighton, & Benet, 1996), and the amounts and activity of various enzymes of the CPY3A family can increase from alcohol consumption (Niemela et al., 1998). In the absence of alcohol, chronic drinkers with increased enzyme activity exhibit increased metabolic rates for medications that are metabolized by cytochrome P450 enzymes. With increased metabolic rates, the concentration of the medication may decline too fast or may be too low for the medication to be effective (Weathermon & Crabb, 1999).

Another potential factor that may influence mifepristone effects on alcohol drinking is subject differences in drinking history or severity of physical dependence on alcohol. Mifepristone reduced alcohol intake in rats that were physically dependent (i.e., exhibited signs of severe withdrawal when alcohol exposure was discontinued), but did not alter alcohol intake in non-dependent rats (Lowery et al., 2010; O’Callaghan, Croft, Jacquot, & Little, 2005; Repunte-Canonigo et al., 2015; Somkuwar et al., 2017; Vendruscolo et al., 2012). For example, in a study by Vendruscolo and colleagues (2015), rats were trained to lever press for alcohol and then half of the rats were exposed to chronic alcohol vapor to induce physical dependence. Mifepristone (30 and 60 mg/kg) administered prior to self-administration sessions dose-dependently reduced alcohol self-administration in the dependent rats, but did not affect alcohol intake in the non-dependent rats. However, mifepristone also has been shown to reduce stress-induced reinstatement of alcohol seeking (Simms et al., 2012) and alcohol drinking under limited-access conditions (Koenig & Olive, 2004) in non-dependent rats. Mifepristone, which is FDA-approved to treat hypercortisolism, has been shown to alleviate behavioral signs of alcohol withdrawal in rodents (Jacquot et al., 2008; Sharrett-Field et al., 2013).

Another factor is development of compulsive-type behaviors associated with drinking. Problematic drinking spans a range of severity. We purposefully developed a model of alcohol misuse, instead of focusing on physical dependence per se, to increase the probability of developing medications to reduce problematic alcohol use in a wider population. Our rationale was based on the fact that alcohol use disorder spans a continuum of drinking severity, with only 5–20% of individuals showing severe signs of withdrawal during abstinence, and suppression of withdrawal symptoms alone is not sufficient for the treatment of alcohol use disorder (Carlson et al., 2012; Manasco, Chang, Larriviere, Hamm, & Glass 2012). In contrast, “at risk” drinking patterns are common across a broader spectrum of alcohol use disorder diagnoses. This differentiation is important as physical dependence develops along a continuum of severity as a function of dose and duration of drug exposure and clinical trials for medications often include a broader range of individuals with alcohol use disorder. Such distinctions may be important in the development of treatments for alcohol use disorder. There has been a conceptual shift in the alcohol field away from separate categorizations of alcohol “abuse” and “dependence,” based in large part on the fact that the term “dependence” for DSM-IV diagnosis of alcohol dependence differs from its historical definition in medical environments as a physiological adaption to chronic drug exposure resulting in a withdrawal syndrome when drug is discontinued. Alcohol physical dependence and withdrawal have been extensively studied in non-human primates and is very similar to what is observed in humans (for review see, Mello, 1973), with severe withdrawal symptoms (tremors/jerks and seizures) observed after discontinuation of chronic 2.6–8 g/kg/day alcohol.

The alcohol self-administration procedures used in the present study do not produce physical dependence. Instead, we developed a model that includes the characteristic drinking patterns of “drinking too much, too fast, and too often” as defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), which is a key feature of alcohol use disorder. Binge drinking (drinking too much, too fast) is defined by NIAAA as alcohol consumption sufficient to achieve a blood alcohol level (BAL) of 80 mg/dL (0.08%) or more within a 2–3 hour drinking period; this corresponds to consumption of 0.8–1 g/kg or about 5 drinks for men and 4 drinks for women. “At risk” drinking also includes drinking an average of more than 14 drinks per week for men and more than 7 drinks per week for women (drinking too much, drinking too often). We have previously shown that baboons drinking at this level show only mild-moderate signs of alcohol withdrawal (e.g., moderate decrease in food intake, increased irritability/aggression) during forced abstinence; tremors/jerks or seizures are not observed. Thus, our baboon model that includes alcohol intake (~1 g/kg per day) sufficient to produce BAL exceeding 0.08% and consumption at this level 7-days/week is comparable to human “at risk” drinking, but not physical dependence. Taken together, the current findings and prior studies (Lowery et al., 2010; O’Callaghan et al., 2005; Repunte-Canonigo et al., 2015; Somkuwar et al., 2017; Vendruscolo et al., 2012) suggest that mifepristone may not decrease daily alcohol intake in drinkers who do not show severe signs of physical dependence. This has important clinical implications as it suggests treatment with mifepristone may not be effective in those who do not show significant levels of physical dependence.

The longevity of non-human primates permits long-term exposure to alcohol-associated cues in the drinking environment and alcohol consumption. Previously we have shown that alcohol-seeking behaviors, which are maintained by alcohol-associated cues, and alcohol-self-administration behaviors are resistant to change (Duke et al., 2014; Holtyn et al., 2014; Kaminski et al., 2012). The baboons will complete high response ratios to obtain the daily supply of alcohol and defend high alcohol intake levels, and show persistent alcohol seeking even during extended abstinence (Holtyn et al., 2014; Kaminski et al., 2008). The long-term drinking history, exposure to alcohol-related cues in the drinking environment, and development of persistent alcohol-directed behaviors are key aspects of human problem drinking and allows for a rigorous assessment of changes in alcohol-maintained behaviors following administration of pharmacotherapies for alcohol use disorder. Importantly, in the same baboons used in the present study, we have shown previously that naltrexone (Holtyn et al., 2017; Kaminski et al., 2012), baclofen (Duke et al., 2014; Holtyn et al., 2017), and varenicline (Kaminski & Weerts, 2014) significantly reduced g/kg alcohol intake under the CSR; highlighting that the model is sensitive to detecting effects similar to those reported in alcohol clinical trials. Mifepristone did not reduce alcohol seeking or self-administration in baboons drinking 1 g/kg daily; level of physical dependence and blood concentrations of mifepristone may be key factors. The current data also suggest substantial variablity in mifepristone concentrations possibly due to capacitiy limited metabolism and, in alcohol drinkers, possible alcohol-inhibited metabolism of orally administered mifepristone, which may have limited effects on alcohol-maintained behaviors.

Supplementary Material

Supplemental Material

Table S1. Effects of mifepristone on responding in the three components of the Chained Schedule of Reinforcement (CSR) for individual baboons (B6-B10).

Table 2B.

Mifepristone plasma levels (ng/ml) following chronic administration of mifepristone in four alcohol-drinking baboons (B6-B9). Each dose was administered for at least 7 days. BQL = Below the Quantifiable Limit.

Dose (mq/kq) Time (hrs) since last dose B6 B7 B8 B9 Mean
10 24 346 BQL 443 26.5 271.8
20 24 448 11.7 264 12.9 184.2
30 1 900 93.5 1490 -- 827.8
30 24 826 1.02 1.05 128 239.0
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Public Significance Statement:

Mifepristone is under investigation as a potential medication for alcohol use disorder treatment. Chronic (7-day) dosing with mifepristone did not reduce alcohol seeking or self-administration in baboons drinking 1 g/kg daily. Pharmacokinetics suggest metabolism of mifepristone may be capacity limited and, in alcohol drinkers, may be inhibited by alcohol consumption.

Disclosures and Acknowledgements

This research was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under Award Number R01 AA015971. Corcept Therapeutics Incorporated gifted mifepristone and paid for independent analysis of plasma samples for the PK studies. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. These funding sponsors were not involved in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Footnotes

Preliminary data were presented at the 2018 annual meeting of the College on the Problems of Drug Dependence (CPDD). The abstract was published and is available in the program abstracts on the CPDD website (CPDD.org).

The authors have no conflicts of interest to report.

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Associated Data

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Supplementary Materials

Supplemental Material

Table S1. Effects of mifepristone on responding in the three components of the Chained Schedule of Reinforcement (CSR) for individual baboons (B6-B10).

NIHMS1048342-supplement-Supplemental_Material.pdf (35.7KB, pdf)

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