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Published in final edited form as: Alcohol Clin Exp Res (Hoboken). 2023 Aug 27;47(10):1943–1951. doi: 10.1111/acer.15163

Influence of social rank on the development of long-term ethanol drinking trajectories in cynomolgus monkeys

Lindsey K Galbo-Thomma 1, April T Davenport 1, Phillip M Epperly 1, Paul W Czoty 1
PMCID: PMC11684457  NIHMSID: NIHMS2041056  PMID: 37553910

Abstract

Background:

Chronic stress contributes to the development of alcohol use disorder (AUD). However, characterizing the role of chronic social stressors in the development of problematic drinking trajectories in humans is complicated by practical and ethical constraints. Group-housed nonhuman primates develop social dominance hierarchies that represent a continuum of social experiences from enrichment in higher-ranked (dominant) monkeys to chronic social stress in lower-ranked (subordinate) individuals. This framework provides a translationally relevant model of chronic social stress that can be used to characterize its effects on vulnerability to AUD.

Methods:

Twelve male cynomolgus monkeys living in three social groups with established social dominance hierarchies were provided access to ethanol and water for 22 h/day, 4–5 days/week, for 1 year. Ethanol-free periods (2- or 3-day “weekends” or longer periods up to 10 days) were spent in social groups to maintain the stability of the social hierarchies. Observational studies conducted 6 months into the year of drinking assessed signs of ethanol withdrawal. After 1 year, monkeys were individually housed 24 h/day, 7 days/week for four consecutive weeks to examine the effect of eliminating the “weekends” spent socially housed.

Results:

Subordinate monkeys had significantly higher mean daily ethanol intakes than dominant monkeys across 1 year of open access. Subordinates also had higher intakes on the first day back drinking following ethanol-free periods of 9–10 days. Moreover, during the last 4 weeks of open access, intakes on the first drinking day after an ethanol-free weekend increased significantly in subordinate monkeys. This effect diminished when all monkeys were individually housed for 4 weeks, indicating that the increased intake in subordinates was driven by the social environment.

Conclusions:

These data demonstrate that social subordination, which is associated with chronic social stress, results in increased vulnerability to the development and maintenance of heavy drinking trajectories.

Keywords: alcohol use disorder, nonhuman primate, social dominance, social stress

INTRODUCTION

Alcohol use disorder (AUD) is a costly and widespread public health problem affecting 28.3 million people 12 years of age and older in the United States. This estimate does not include individuals meeting criteria for other problematic drinking behaviors, such as binge and heavy drinking (Substance Abuse and Mental Health Services Administration, 2021). Environmentally derived stress is a well-established risk factor for the development of AUD (Blaine & Sinha, 2017; Sinha, 2008). Low-socioeconomic status, poor familial or social relationships, and lack of access to resources result in dysregulation of the physiological stress response, changes in brain structure and function, and higher rates of morbidity, including AUD, and mortality (Blaine & Sinha, 2017; Galea & Vlahov, 2002). Although a great deal has been learned about the interactions between chronic alcohol drinking and stress systems, ethical and practical concerns make it difficult to characterize how chronic social stress influences the development of individual alcohol drinking trajectories in humans. Laboratory animal models with high construct and predictive validity would be of great value in addressing this critical knowledge gap.

Nonhuman primates (NHPs) provide the most translationally relevant animal model for investigating the complex relationship between stress and ethanol consumption due to their similarity to humans in the brain structure and function, neuroendocrinology, pharmacokinetics, metabolism, genetics, and their ability to form complex social relationships (Jimenez & Grant, 2017; Nader et al., 2012; Phillips et al., 2014; Weerts et al., 2007). Group-housed monkeys form social hierarchies representing a continuum from social enrichment in the highest-ranked (dominant) monkeys to chronic social stress in the lowest-ranked (subordinate) monkeys (Nader et al., 2012). Like humans who experience chronic stress, subordinate monkeys have increased rates of morbidity and mortality related to a variety of conditions (Goymann & Wingfield, 2004; Kaplan et al., 1982; Sapolsky, 2005). Importantly, social variables have been shown to influence sensitivity to psychoactive drugs, including ethanol (Helms et al., 2012; McKenzie-Quirk & Miczek, 2008; Morgan et al., 2002; Nader et al., 2012). Monkeys voluntarily drink ethanol at rates of intake similar to humans, developing stable individual drinking phenotypes (e.g., low, binge, or heavy consumption). The high validity of NHP models enables longitudinal examination through various stages of consumption, such as ethanol-naïve, -consuming, and -free (abstinent) states (Baker et al., 2014; Jimenez & Grant, 2017; Vivian et al., 2001). For these reasons, group-housed monkeys that voluntarily consume ethanol are the most translationally relevant animal model for understanding mechanisms involved in vulnerability to AUD and the subsequent effects of this phenotype on health and behavior. The present study combined NHP models of social stress and ethanol self-administration to evaluate how rank in the NHP social hierarchy influences the development of individual drinking trajectories.

Previous studies in NHPs support the view that subordination stress leads to an increase in ethanol consumption. Studies reported greater ethanol intakes in subordinate macaques living in groups of three or four (Helms et al., 2012) and squirrel monkeys living in multi-generational, mixed-sex groups of 4–10 monkeys (McKenzie-Quirk & Miczek, 2008). The present studies were conducted in adult male cynomolgus monkeys who had been transitioned to group housing and trained to drink escalating doses of ethanol using schedule-induced polydipsia (Galbo et al., 2022). The present study characterized more than 1 year of ethanol drinking under “open-access” conditions in which monkeys had relatively unrestricted access to ethanol (22 h/day, 4–5 days/week). It was hypothesized that subordinate monkeys would exhibit higher average daily ethanol intakes than dominant monkeys.

Once monkeys completed 1 year of open access to ethanol, additional studies were conducted to assess whether any rank-related differences were influenced specifically by the social environment. First, we examined whether dominant and subordinate monkeys drank different amounts of ethanol on the first day back drinking after 2-day ethanol-free “weekends.” It was hypothesized that subordinates, having experienced social stress during this time off from drinking, would show increases in ethanol intake compared to dominant monkeys when the next drinking opportunity occurred. We also examined drinking on the first day back under the same regimen (5 consecutive days of drinking, 2 days off) while monkeys were individually housed for 24 h/day, 7 days/week (except to eat) for 1 month. It was hypothesized that removing social interactions entirely would attenuate any rank-related differences in ethanol intake. Finally, to examine the possibility that rank-related differences in ethanol intake were due to dominant and subordinate monkeys developing a different degree of ethanol dependence, we conducted observations to identify any signs of withdrawal.

MATERIALS AND METHODS

Subjects

Twelve adult male cynomolgus monkeys (Macaca fascicularis, 12.5 ± 2.1 years of age at the start of the study) served as subjects. At the outset of these studies, monkeys lived in groups of four in stainless-steel cages (172.5 cm high × 171.5 cm wide × 69.9 cm deep; Allentown Caging) in which water was available ad libitum. Monkeys could be individually housed by dividing the cage into quadrants (each measuring 81.2 cm high × 80.6 cm wide × 69.9 cm deep) by inserting wire mesh partitions. All procedures and experiments described herein occurred in this setting. Periods of social housing were started by the removal of these partitions, and periods of individual housing, during which all feeding and ethanol self-administration occurred, were begun by the insertion of the partitions. Monkeys were weighed every other week and fed enough food (Grain-Based Dustless Precision Pellets, Bio-Serve), fresh fruit, and vegetables daily to maintain healthy body weights and body scores without becoming obese, as determined by daily inspection and periodic veterinary examinations. On ethanol self-administration days, monkeys earned their daily pellet ration during the session (see below). On days that no ethanol self-administration session occurred, monkeys were individually housed at approximately 11:00 a.m., the daily ration of pellets was given, and monkeys were allowed approximately 2 h to consume the pellets before partitions were removed. Body weights did not differ significantly between dominant and subordinate monkeys at any point in the study and did not change systematically in either group, regardless of ethanol intake.

Apparatus

Monkeys had been trained to use an operant drinking panel affixed to each quadrant of the cage for ethanol, water, and food self-administration (Galbo et al., 2022). Briefly, each panel included three lights (red, amber, green) above each of two drinking spouts, a photo-optic switch below one spout to respond for delivery of 1 g food pellets, and an opening in the center of the panel containing a white light and a dowel that was pulled to allow the flow of ethanol or water. Each drinking spout was connected to a 2 L bottle containing either ethanol (4% w/v) or water, each of which sat atop a balance that continuously monitored the bottle’s weight which was converted to volume. Amber lights indicated the start of the session and that the panel was active, green lights illuminated when the dowel was pulled and during fluid flow, and red lights illuminated when food pellets were available. Animal housing, handling, and all experimental procedures were performed in accordance with the 2011 edition of the National Research Council’s Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of Wake Forest University. Environmental enrichment was provided as outlined in the Committee’s Nonhuman Primate Environmental Enrichment Plan.

Social rank determination

Social ranks had been determined previously (Galbo et al., 2022). Briefly, monkeys were randomly assigned to three pens (Pens A, B, and C) by weight. The three heaviest monkeys were designated to three separate pens, then the next three heaviest were randomly placed into those pens, and so on. Social ranks were determined over 12 weeks via video observation based on outcomes of dyadic aggressive and submissive interactions (Czoty et al., 2009; Kaplan et al., 1982; Morgan et al., 2000). The monkey in each pen aggressing toward all others and submitting to none was ranked #1 (most dominant). The #2-ranked monkey aggressed toward all but the #1-ranked monkey and submitted only to him. The #3-ranked monkey aggressed toward only the #4-ranked monkey and submitted toward the other pen-mates. The monkey that displayed the lowest frequency of aggressive behaviors and submitted to all other monkeys in the pen was designated the most subordinate (#4). For the duration of the study, social rank was informally assessed by observing interactions between all monkeys in the pen when group-housed. Social ranks remained stable in Pens A and C for the duration of the study; #1- and #2-ranked monkeys were considered dominant, and #3- and #4-ranked monkeys were considered subordinate (dominant, n = 4; subordinate, n = 4). In Pen B, a fight occurred between the two dominant monkeys (8493, #1, and 8501, #2) 11 weeks into the open access period that necessitated that the monkeys be separated for veterinary care. Over the next 7 weeks, repeated attempts at reintroduction were unsuccessful. Thus, these four monkeys lived in two pairs (8501 and 8528, 8493 and 8527) for the duration of the study. A dominant and subordinate monkey was identified in each pair (dominant, n = 2; subordinate, n = 2). The week that ethanol access resumed is considered week 12 for this group. Due to the difference in housing conditions (pairs vs. groups of 4) and the 7-week break from ethanol drinking, Pen B data are presented separately from those of Pens A and C.

Ethanol self-administration

Monkeys had been trained to orally self-administer ethanol using a well-established procedure of schedule induction (Galbo et al., 2022; Vivian et al., 2001). Following induction, monkeys had access to a 4% ethanol solution and water 22 h/day, 4–5 days/week (“open access”). Sessions began at 11:00 a.m. on weekdays with the illumination of cue lights above the ethanol and water spouts and ended at 9:00 a.m. the following day. Throughout the session, ethanol, and water were freely available when the dowel was pulled. Monkeys also self-administered food pellets under a one-response fixed-ratio (FR 1) schedule of reinforcement using the photo-optic switch. The daily food pellet allotment (based on the monkey’s weight) was divided into three “meals,” which began 0, 120, and 240 min after the start of the session. Each meal lasted until one-third of the daily ration had been delivered or until the next meal period began. The average (± SEM) number of drinking sessions over 1 year of open access was 196.0 ± 1.5. Mesh partitions separated monkeys during ethanol self-administration sessions, allowing for visual, olfactory, auditory, and limited tactile contact with pen-mates. To determine if there were differences in mean daily ethanol and water intakes each week over 1 year of open access, a two-way repeated-measures ANOVA was performed with social rank (dominant, subordinate) and week (1 through 52) as factors, followed by post-hoc Sidak multiple comparisons tests. The same analysis was performed to analyze cumulative ethanol intake, and an unpaired t-test was performed to determine rank-related differences in ethanol intakes over the entire year, and over the last month of the year.

Drinking after ethanol-free periods of different lengths

As described above, monkeys were individually housed on days of ethanol self-administration (4–5 days/week) and group-housed on non-drinking days (2–3 consecutive days/week). Occasionally throughout open access, monkeys spent extended periods of time (4–10 days) group-housed due to study-related events, holidays, etc. These ethanol-free periods were grouped into bins (2–3, 4–5 or 9–10 days), and the amount of ethanol consumed on the first subsequent day of drinking (the “day back”) was compared to the mean of the previous week (the “week prior”) using a two-way repeated-measures ANOVA with rank and time as factors and post-hoc Sidak multiple comparisons tests where appropriate. Pen B dominant and subordinate monkeys were included in this analysis.

One month of individual housing

Near the end of open access, we observed greater increases in ethanol intake on the day back drinking following the shorter (2–3-day) ethanol-free periods in the subordinate monkeys in Pens A and C. A two-way repeated measures ANOVA with rank and time as factors was performed to compare mean ethanol intakes of the previous week (the “week prior”, excluding the first day back drinking) to intakes the first subsequent day of drinking (the “day back”), as described above, for the last 4 weeks of open access, followed by post-hoc Sidak multiple comparisons tests. To examine if this effect was due to social interactions, monkeys in Pens A and C were then separated 24 h/day, 7 days/week for 1 month during both ethanol self-administration (5 days/week) and non-drinking days (2 days/week), and the same analysis was conducted. Solid partitions were placed between quadrants of the home cage, preventing visual and tactile contact with pen-mates, but permitting interactions with monkeys of pens located across the study room.

Assessment of signs of ethanol withdrawal

Approximately 6 months into the open-access period, when drinking patterns had stabilized, each monkey was assessed for signs of ethanol withdrawal. Assessments were performed for each monkey at four time points: prior to the start of the last drinking session of the week, 6 h after the start of that session, and 24 h from each of these timepoints on the subsequent non-drinking day. One observer spent 2 min conducting in-room observations of monkeys, then started a video camera prior to exiting (Table 1). Two observers then scored 10-min videos for the presence, absence, and/or frequency (items marked with an asterisk in Table 1) of behaviors associated with ethanol withdrawal, using a rubric adapted from Cuzon Carlson et al. (2011). Two of the heaviest drinkers were re-assessed at the end of the open access period. Inter-rater reliability for video measurements was calculated as the percent of observations for which a discrepancy was observed.

TABLE 1.

Behaviors monitored used as indicators of ethanol withdrawal as assessed in the colony room or via video.

In-room observations
Physiological: spontaneous tremor, tremor when reaching for a treat, piloerection
Other behaviors: teeth grinding, latency to retrieve treat, intentional tremor when retrieving treat, abnormal behaviors
Video observations
Physiological: emesis, anorexia (eating less than daily allotment of pellets)
Anti-social behaviors: huddling (hugging body with head down), low affect (withdrawn from social group and indifferent to stimuli)
Operant behaviors: dowel pull,* interaction with ethanol spout,* interaction with water spout*
Displacement behaviors: scratch,* body shake*
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Note: Behaviors marked with an asterisk indicate that the frequency of the behavior was assessed. Otherwise, the presence or absence of the behavior was scored.

RESULTS

Effect of social rank on individual drinking patterns

Demographics and individual monkeys’ daily and lifetime ethanol intakes are summarized in Table 2. During 1 year of open access to ethanol and water, subordinate monkeys in Pens A and C had significantly higher mean ± SEM daily ethanol intakes (1.95 ± 0.42 g/kg) than dominants (0.46 ± 0.15 g/kg; Figure 1, top left panel). A two-way repeated-measures ANOVA indicated a significant main effect of rank (F1,6 = 11.92, p < 0.05), but not week, and a significant interaction (F49,294 = 1.44, p < 0.05). A post-hoc Sidak multiple comparisons test did not identify any single week in which the ranks differed. When the same analysis was performed on data from only the final 4 weeks of the year of open access self-administration a significant main effect of rank was again observed (F1,6 = 7.02, p < 0.05). A two-way repeated measures ANOVA of cumulative intake over 1 year of open access for Pens A & C (Figure 1, bottom left) also indicated significant main effects of time (F1.15,6.92 = 25.68, p < 0.005) and rank (F1,6 = 11.85, p < 0.05) and a significant interaction (F49,294 = 9.56, p < 0.0001). An unpaired t-test indicated that subordinates had significantly greater lifetime ethanol intakes (477.48 ± 90.57 g/kg) than dominants (182.85 ± 26.91 g/kg; t6 = 3.12, p < 0.05) after 1 year of self-administration. In contrast, no significant differences were observed between dominants and subordinates in mean daily water intake, or when ethanol intake was compared between monkeys when divided into four ranks (data not shown). In Pen B, dominants had greater mean daily ethanol intakes (1.59 ± 0.54 g/kg) than subordinates (1.07 ± 0.18 g/kg; Figure 1, top right), but the ANOVA revealed no statistically significant main effects of rank or time and no interaction. Regarding cumulative intake in Pen B (Figure 1, bottom right), there was a main effect of time (F50,100 = 20.14, p < 0.0001), but not rank or an interaction. Lifetime intakes at the end of open access did not significantly differ (dominants, 422.30 ± 99.27; subordinates, 326.53 ± 35.77).

TABLE 2.

Subject demographics.

Monkey ID Rank Mean ± SD weight (kg) Age (years) at onset of drinking Mean daily intake ± SD (g/kg) Lifetime intake (g/kg)
8491A 1 8.21 ± 0.12 13.3 0.64 ± 0.59 223.60
8490A 2 7.65 ± 0.40 13.3 0.74 ± 0.73 207.97
8497A 3 6.84 ± 0.08 13.3 2.94 ± 1.29 694.11
8496A 4 7.62 ± 0.31 13.3 2.32 ± 0.97 550.51
8493B D1 8.16 ± 0.22 13.3 1.05 ± 0.77 329.98
8527B S3 7.26 ± 0.19 9.8 0.90 ± 0.57 294.17
8501B D2 7.82 ± 0.30 13.3 2.13 ± 0.89 521.61
8528B S4 8.19 ± 0.31 8.8 1.25 ± 0.68 369.43
8494C 1 7.08 ± 0.24 13.3 0.04 ± 0.06 103.94
8108C 2 5.84 ± 0.13 10.6 0.47 ± 0.53 195.89
8495C 3 6.87 ± 0.19 13.3 1.42 ± 0.92 378.57
8500C 4 7.46 ± 0.18 13.3 1.11 ± 0.63 286.71
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Note: Superscript letter indicates pen. Rank number (for pens of four monkeys) or letter (for pairs) indicates dominant (1, 2, D) or subordinate (3, 4, S). For monkeys in Pen B, rank prior to being placed into pairs is indicated by the superscript.

FIGURE 1.

FIGURE 1

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Mean (± SEM) daily ethanol (EtOH) intakes per week (top row) and cumulative intakes (bottom row) for dominant (DOM) and subordinate (SUB) monkeys in Pens A and C (left panels; n = 4 per rank) and B (right panels; n = 2 per rank) over 1 year of open access to ethanol and water. Points above IND indicate intakes at the end of the induction period. Break in the x-axis of the right column of panels marks the 6.5-week ethanol-free period in which Pen B group reintroductions were attempted.

Effects of ethanol-free periods

To assess changes in ethanol intake following ethanol-free periods during 1 year of drinking, ethanol-free periods that occurred throughout the year were grouped by 2–3, 4–5, or 9–10 days. There was a mean of 49.0, 11.2, and 4.7 observations, respectively, in those bins. A two-way repeated measures ANOVA indicated significant main effects of bin (F2,20 = 5.69, p < 0.05) and rank (F1,10 = 6.84, p < 0.05) and a significant interaction (F2,20 = 4.52, p < 0.05). A Sidak, multiple comparisons test, indicated a significant difference between dominants and subordinates for 9–10-day ethanol-free periods (t30 = 3.89, p < 0.005; Figure 2).

FIGURE 2.

FIGURE 2

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Mean (± SEM) changes in ethanol intake in dominant and subordinate monkeys following ethanol-free periods of various lengths throughout 1 year of open access (**p < 0.005).

Effects of 1 month of individual housing

When comparing the mean ethanol intakes from the week prior and day back drinking in dominant and subordinate monkeys in Pens A and C over the last 4 weeks of open access, a two-way repeated measures ANOVA identified a significant main effect of rank (F1,6 = 9.93, p < 0.05; Figure 3A) but not time and a significant interaction between time and rank (F1,6 = 10.80, p < 0.05). A Sidak multiple comparisons test confirmed that ethanol intake on the first day back drinking was significantly different (p < 0.05) in subordinate, but not dominant, monkeys. Furthermore, dominant and subordinate monkeys had significantly different mean ethanol intakes at both timepoints (week prior, p < 0.05; day back, p < 0.01). When monkeys were individually housed for 1 month, the same analyses did not identify the main effects or an interaction of time and/or rank (Figure 3C).

FIGURE 3.

FIGURE 3

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Group (a, c) and individual (b, d) mean (± SEM) ethanol intakes in dominant (DOM) and subordinate (SUB) monkeys during the week prior (“Wk prior”; excludes first day of the week) to a 2-day ethanol-free period and the next drinking day (“Day back”) drinking over the last 4 weeks of open access (panels a and b) and when individually housed for 1 month (panels c and d). (*p < 0.05).

Assessment of ethanol withdrawal signs

Regarding in-room observations, no signs of ethanol withdrawal were observed. The latency to retrieve a treat was always less than 4 s. No emesis, anorexia, tremors, piloerection, teeth grinding, or abnormal behaviors were observed in any monkeys at any time point. On the non-drinking day, video observations indicated a slight increase in the amount of time spent huddling for five monkeys, but this was unrelated to rank, ethanol intake on the previous day, or time point. Only one monkey showed more than one body shake (3). Seven monkeys interacted with the dowel switch, and four interacted with spouts but not more than twice; these were unrelated to rank, ethanol intake, or time point. When reassessed at the end of open access, the two heaviest drinkers (both subordinates) showed no withdrawal signs. Inter-rater reliability for video observations was 3.2%.

DISCUSSION

The present studies characterized how position in the NHP social dominance hierarchy influences the development of individual drinking patterns over 1 year of open access to ethanol and water. Subordinate monkeys had higher mean daily ethanol intakes than dominant monkeys. This result is consistent with a previous study using the same drinking model in male cynomolgus monkeys that alternated between individual and group housing (Helms et al., 2012) and an earlier cross-sectional study of mixed-sex groups of squirrel monkeys with limited (15 min) daily access to ethanol (McKenzie-Quirk & Miczek, 2008). Unlike those studies, monkeys in the present study lived in stable social groups for nearly 3 years (except for Pen B). In this way, the present data extend the conclusions of previous studies to long-term, stable NHP social hierarchies and long-term, unrestricted access to ethanol. Throughout the year, subordinate, but not dominant monkeys, increased their ethanol intakes following long (9 or 10 days) ethanol-free periods during which monkeys were group-housed. By the end of 1 year of open access, subordinate monkeys showed greater increases in ethanol intake following 2 or 3 days off from ethanol self-administration as well. When monkeys were individually housed for 1 month, however, this effect dissipated. Taken together, these findings support the conclusion that social rank-related differences in ethanol intakes were driven by social factors.

The observed increases in ethanol intake in subordinate monkeys after time off from ethanol access is reminiscent of the “alcohol deprivation effect” observed in rodents and monkeys (Korney et al., 1990; Rodd et al., 2004; Sinclair, 1971). There are several suggested mechanisms for this effect, including prime- or cue-induced reinstatement or increased responding in anticipation of future events (Heyser et al., 1997). In the present study, all monkeys were exposed to the same voluntary self-administration parameters and the same time off from ethanol access, yet only subordinates showed an increase in drinking on the day after a break. Moreover, even our heaviest-drinking monkeys did not show withdrawal signs, suggesting that none of the monkeys were dependent on ethanol. Therefore, it is unlikely that the increase in drinking on the day after the break involves negative reinforcement related to the relief of a dysphoric withdrawal state. Considering that the difference in subordinates’ drinking on the day back from a break was dependent on being housed socially during the break, it is tempting to speculate that anxiolytic effects of ethanol may have played a role. Regardless of the behavioral mechanism driving the increased responding after time off, the present results indicate that the “alcohol deprivation effect” is not a unitary phenomenon, but rather can be influenced by social experience during the ethanol-free period.

Across many social settings, including the one used in the present studies (Czoty et al., 2009; Galbo et al., 2022; Morgan et al., 2000), subordinate monkeys experience chronic stress as a result of receiving aggression and non-physical intimidation, low access to resources, inability to escape the setting and a lack of social support. Observations collected during the establishment of the social hierarchies of the present cohort (Galbo et al., 2022) and the long-term stability of two of the hierarchies suggest that to be the case in this group as well. In both rodents and NHPs, social subordination can alter hypothalamic–pituitary–adrenal axis function (Blanchard et al., 1993; Higley et al., 1992; Sapolsky et al., 1997; Shively, 1998). However, while increases in circulating concentrations of corticosterone/cortisol are a reliable response to an acute stressor, neuroadaptations to chronic stress make it a less reliable measure of chronic stress. For example, in a previous study of male cynomolgus monkeys in the same experimental social setting, cortisol concentrations were elevated during the first day of social housing in all monkeys; the effect was greater in monkeys who would eventually become subordinate (Czoty et al., 2009). However, this effect dissipated within 3 days. Moreover, when circulating cortisol was measured 12 weeks later, when hierarchies had stabilized, there were no rank-related differences. For this reason, we chose not to measure cortisol concentrations as an index of social stress in the present studies.

Through extensive studies with multiple cohorts of monkeys who experienced this AUD model, Grant and colleagues have used sophisticated analyses to define phenotypic categories of ethanol drinking (light, binge, heavy, and very heavy) and have demonstrated long-term stability of these categories in individual monkeys (Baker et al., 2014; Vivian et al., 2001). Using these categories, the intake of one subordinate monkey (8497, 2.94 g/kg) nearly met the criteria as a heavy drinker (>3.0 g/kg), and one subordinate (8496) and one dominant (8501) monkey met criteria as binge drinkers (>2.0 g/kg). All other monkeys in the present study met the criteria as light drinkers (<2.0 g/kg). Thus, the ethanol intakes of the present cohort were qualitatively and quantitatively lower than those of several previous cohorts of macaques. One possible explanation involves housing conditions; the cohorts of monkeys in whom Grant and colleagues defined these categories were individually housed. A subsequent study from this group found that ethanol intakes were slightly lower when monkeys were housed for 24 weeks in groups of three or four compared to when they were individually housed for 23 weeks (Helms et al., 2012). Taken together, these and the present results suggest that being socially housed—even for subordinate monkeys—is less stressful than never having social contact. It is also worthy of note that although only one monkey nearly met the Baker et al. (2014) criterion for heavy drinking, seven of the eight monkeys drank more than 1.0 g/kg (equivalent to four drinks per day), which exceeds the National Institute on Alcohol Abuse and Alcoholism’s definition of “heavy alcohol use” (>4 drinks or 1.0 g/kg per day in men).

Another possible explanation for the lower levels of ethanol consumption in the present study compared to previous reports involves the age at which monkeys first began drinking. In a previous study, monkeys first experienced ethanol during adolescence or young adulthood (4.0–4.6 years and 5.0–5.6 years, respectively; Helms et al., 2014). These monkeys became heavier drinkers, with mean ethanol intakes of 3.2 and 2.5 g/kg, respectively, whereas monkeys who began drinking in middle adulthood (6.9–9.7 years) had a mean intake of 1.7 g/kg. These relationships resemble studies examining the influence of age at the onset of drinking in humans (Dawson et al., 2008; Grant et al., 2001, 2006; Helms et al., 2014). Subjects in the present study were 12.5 ± 2.1 years old at the outset of the study and had similar ethanol intakes as adult monkeys in the Helms et al. (2014) study. Interestingly, daily ethanol intakes of subordinate monkeys in the present study (mean ± SEM 1.95 ± 0.42 g/kg, range 1.11 to 2.94 g/kg), were higher than the adult-onset monkeys in Helms et al. (2014). Taken together, these distributions suggest that social subordination enhances vulnerability to heavy drinking, even in monkeys who start drinking later in adulthood. It must be pointed out, however, that the monkeys in the present study were all male; the same conclusions may not apply to female monkeys.

In summary, these data demonstrate that subordinate monkeys living in stable social hierarchies develop individual drinking patterns comparable to humans who meet the criteria for problematic drinking behaviors or AUD and support a causal role for social experience in these effects. Our data also support the view that age at the onset of drinking is an important factor in vulnerability to the development of AUD. Finally, subordinate monkeys were found to have increased ethanol intakes following ethanol-free periods spent in their social environment, as opposed to spending time alone, which further implicates social stress as a driving environmental factor in problematic drinking.

ACKNOWLEDGMENTS

The authors thank Santiago Saldaña and Miracle Collier for their contributions to program development and data collection, and Dr. Kathleen Grant for helpful conversations regarding data interpretation.

FUNDING INFORMATION

This work was supported by the National Institutes of Health and the National Institute of Alcohol Abuse and Alcoholism (P50 AA 26117, T32 AA 07565, F31 AA 029588).

Footnotes

CONFLICT OF INTEREST STATEMENT

The authors have no conflicts of interests to disclose.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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