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Transl Psychiatry
Transl Psychiatry
Translational Psychiatry
2158-3188
Nature Publishing Group UK London

39261461
3076
10.1038/s41398-024-03076-7
Article
Oxytocin decreases alcohol self-administration in male baboons
Lee Mary R. 1
http://orcid.org/0000-0003-0198-4788
Moore Catherine F. 2
http://orcid.org/0000-0002-8234-0919
Weerts Elise M. eweerts@jhmi.edu

2
1 grid.413721.2 0000 0004 0419 317X Veterans Affairs Medical Center, Washington, DC USA
2 grid.21107.35 0000 0001 2171 9311 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD USA
11 9 2024
11 9 2024
2024
14 3697 3 2024
21 8 2024
27 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
The neurohormone oxytocin (OT) has been proposed as a treatment for alcohol and nicotine use disorders. The aim of the present study was to examine whether intravenous (IV) OT decreases alcohol oral self-administration and consumption in nonhuman primates under a 6-h alcohol access procedure as well as alcohol and nicotine (IV) self-administration under 6-h concurrent access conditions. The subjects were five male baboons (Papio anubis) that self-administered oral alcohol (4% w/v) during 6-h sessions under a fixed ratio 3 (FR3) schedule per drink. Baseline levels of alcohol self-administration were established and then OT treatment was initiated. A single dose of OT (20, 40, 80, 120 IU, IV) or its vehicle (saline) was administered before and again in the middle of the 6-h drinking session for 5 consecutive days (total oxytocin dose of 40, 80, 160, 240 IU/day). After each 5-day treatment, baseline levels of alcohol self-administration were reestablished before the next 5-day OT treatment. In addition, the effect of OT on concurrent alcohol and IV nicotine self-administration was explored in 3 of the baboons where alcohol and nicotine were concurrently available during the 6-hr session each under an FR3 schedule for each drug. Establishment of baseline self-administration and 5-day OT treatments were completed as in the alcohol only study. There was a significant overall reduction in alcohol consumption with OT compared to placebo. On post-hoc analysis, after correcting for multiple comparisons, the 40 and 80 IU doses of OT significantly reduced alcohol consumption compared with vehicle, and consumption did not vary significantly within each 5-day treatment period. OT, qualitatively, also reduced the coadministration of both alcohol and nicotine in each baboon for at least one of the OT doses administered. These results underscore the therapeutic potential of oxytocin as a treatment of alcohol use disorder and possibly, co-use of nicotine.

Subject terms

Clinical pharmacology
Physiology
https://doi.org/10.13039/100000027 U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAAA) R01AA015971 Weerts Elise M. Bench-to-Bedside (B2B) Grant (MRL) funded by the NIH Office of Behavioral and Social Sciences Research (OBSSR)Bench-to-Bedside (B2B) Grant (MRL) funded by the NIH Office of Behavioral and Social Sciences Research (OBSSR).issue-copyright-statement© Springer Nature Limited 2024
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pmcIntroduction

Oxytocin (OT) is a peptide hormone synthesized in the magnocellular neurons of the paraventricular (PVN), supraoptic (SON) and accessory magnocellular (AN) nuclei of the hypothalamus and released into the bloodstream from axon terminals of these neurons which are in the posterior pituitary. In addition to acting as a hormone on peripheral targets to promote uterine contraction and lactation, OT acts centrally via dendritic release as well as terminal release from fibers projecting from the SON and PVN to mesocorticolimbic regions.

On the strength of a large body of preclinical research, OT has been proposed as a treatment for various neuropsychiatric disorders [1], including alcohol and drug use disorders [2]. OT modulates several key systems involved in addiction processes, including opioid and dopamine mesolimbic reward circuitry, and hypothalamic–pituitary–adrenal (HPA) axis and corticotrophin-releasing factor (CRF) stress systems [3, 4]. Of particular interest is the role of OT in associative learning and memory, each of which are involved in drug seeking and reinforcement and the development of drug tolerance [4, 5]. OT may disrupt alcohol-associated learned responses and neuroadaptive changes associated with long-term alcohol exposure.

In rodent models, OT decreased alcohol preference and seeking, and produced long-term decreases in alcohol reinforcement [4, 6–8]. Intracerebroventricular administration of OT reduced alcohol self-administration and attenuated reinstatement of alcohol seeking in rats [9]. Intranasal OT blocked alcohol self-administration and motivation for alcohol in alcohol-dependent rats acting centrally at the OT receptor [10]. In addition to its effects on alcohol-directed behaviors, OT may be useful for alcohol withdrawal following abstinence. In rodent models, OT attenuated the development of rapid tolerance to the hypothermic, hypnotic, myorelaxant effects of alcohol and decreased alcohol withdrawal [4, 11–16].

In a small randomized placebo-control clinical trial in alcohol dependent subjects [17], intranasally delivered OT compared to placebo attenuated craving associated with early abstinence and reduced the quantity of benzodiazepines required for the treatment of alcohol withdrawal. Interestingly, OT also has been shown to reduce several behaviors related to nicotine addiction such as cigarette consumption [18] and cue-induced craving [19], but see [20, 21], with a previous rodent study reporting that OT blocks physical symptoms of withdrawal from nicotine [22].

Nonhuman primate models of alcohol self-administration provide an important translational bridge in drug development from rodents to humans for treatment of alcohol use disorder (AUD). Rodent brain distribution of OT receptors is different from that in primate species [23] and nonhuman primates have similar alcohol metabolism to humans. Our group has a long history of testing potential medications for the treatment of AUD in baboons using our chained schedule of reinforcement (CSR) procedure which models the distinct sequence of alcohol seeking leading to alcohol consumption [24–28]. This limited alcohol access procedure is sensitive to medications that have demonstrated a significant reduction of alcohol consumption in human studies (e.g., varenicline, baclofen and naltrexone).

To expand our medications testing of potential AUD medications under longer alcohol access conditions we recently developed a 6-h alcohol access procedure that included an alcohol and nicotine concurrent access (ANCA) paradigm in baboons [29]. While continuous 24-h alcohol access may appear to have good face validity, prior studies have shown that cyclic patterns of intake emerge in which very high intake is followed by periods of abstinence [30], and thus would have limitations for efficient evaluation of medications. Alternatively, limited extended alcohol access (6-hrs/day) produces stable day-to-day alcohol intake and thus allows clear detection of changes in behavior and alcohol intake, while modeling key characteristics of human ‘at risk’ heavy drinking and permit testing of medications to reduce alcohol drinking.

In developing our procedure, we utilized a low response cost, as drug self-injection under low response schedules is highly dose-dependent, with higher doses maintaining less frequent injections. This is particularly relevant for drugs like nicotine that are weak reinforcers [31]. In this highly novel procedure, alcohol drinks and nicotine injections are concurrently available under a fixed ratio 3 (FR3) schedule of reinforcement (low response cost) during daily 6-h sessions. With these parameters, reliable self-administration of alcohol and nicotine were demonstrated under the 6-h extended access procedure under single and concurrent access conditions, and the quantity of alcohol and nicotine during co-self-administration was comparable to the consumption of each drug alone and at levels comparable to human intake [29]. Using this model, we also demonstrated that varenicline, an FDA-approved medication for smoking cessation, significantly reduced intake of both alcohol and nicotine when compared to the vehicle condition [29]. Since primate species, human and nonhuman, share common mechanisms of nicotine and alcohol metabolism, they provide an important translational bridge in drug development [32].

The current study evaluated the effects of IV OT on alcohol drinking and consumption under conditions of extended (6-h) alcohol access (Experiment 1) and under conditions of concurrent access to both alcohol and IV nicotine (Experiment 2).

Methods

Subjects and apparatus

Subjects were five, unrelated adult male baboons (Papio anubis), weighing 24.3 to 33.6 kg at the beginning of experiments, with prior experience with alcohol self-administration. Table 1 shows subject characteristics (approximate age, body weight, years of alcohol drinking experience, average alcohol intake, years of nicotine experience, and average nicotine intake). Baboons were individually housed in standard primate cages modified to serve as the experimental chambers; each cage had a bench that ran along one side wall and an aluminum intelligence panel mounted on the rear wall, within easy reach of the baboon when seated on the bench. The baboons were fed standard primate chow adjusted to maintain sufficient caloric intake (e.g., 50–73 kcals/kg), 2 pieces of fresh fruit or vegetables (70–120 g each), and a children’s chewable multivitamin daily. Tap water from a drinking spout located on the front of the cage was continuously available 24 h per day and water intake was recorded daily at the same time each day (8:30 AM). The housing room was maintained under a 12-h 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.Table 1 Study subject characteristics.

ID	Approximate age (yr)	Body Weight (kg)	Alcohol experience at study start (yr)	Baseline Alcohol Intake (g/kg)	Nicotine experience (yr)	Baseline nicotine intake (mg/kg)	
BV	28.0	24.9	4.6	1.95	–	–	
BS	28.3	24.3	6.7	0.91	–	–	
GG	19.8	33.6	4.6	1.25	1.3	0.81	
CY	22.0	27.0	4.3	1.85	0.04	1.80	
SK	21.9	24.5	1.2	0.79	0.6	1.32	

For each baboon, the intelligence panel contained two vertically operated levers, two different colored jewel lights mounted above each lever, and a custom drink-o-meter (Kandota Instruments, Sauk Center, MN) with two white and two green lights surrounding a protruding drink spout in the upper left quadrant of the panel. The alcohol solution was in a calibrated 2000 ml bottle positioned on the grating above the cage and connected to the drink-o-meter. The intelligence panel also contained a 5 × 5 cm light panel (bay light), and a speaker for delivery of white noise and tones mounted behind the panel. Experimental control and data collection were accomplished using computers with MED Associates Inc. (East Fairfield, VT) software and instrumentation that were connected to the intelligence panel on the outside of the cage.

Baboons had experience self-administering alcohol alone or concurrently with nicotine using the same procedures as the current study (see Table 1). Baboons were surgically implanted with a chronically indwelling intravenous (IV) catheter protected by a tether/harness/vest system, which allowed unrestricted movement within the cage. Full details (including a figure) of the cage, the intelligence panel configuration, and the vest/tether/infusion system are provided in our prior publication of these methods [29].

Briefly, the tether and catheter were connected to a liquid swivel, mounted on the top of the cage. The swivel was connected to a custom valve system and three separate peristaltic infusion pumps (Model 1201 or Model 66 Harvard Apparatus, Natick, MA). Intravenous solutions (nicotine or saline) were injected into the catheter via one pump and followed by a saline flush into the vein using a second pump. To maintain catheter patency, a third pump continuously infused approximately 250 ml of heparinized saline (5–10 units/ml). The peristaltic pumps, infusion systems, and drug solutions were located on a metal grating above the cage. Baboons were anesthetized every 2–3 weeks with ketamine hydrochloride (preceded by atropine sulfate) to permit cage washing, weighing, physical examinations, and catheter care. The experimental protocol was approved by the Johns Hopkins University Animal Care and Use Committee.

Drugs

Ethyl alcohol (190 Proof; Pharmco-AAPER, Brookville, CT) was diluted with reverse osmosis purified drinking water to a concentration of 4% w/v alcohol. Nicotine hydrogen tartrate (Sigma/Aldrich, St. Louis, MO, and NIDA Drug Supply Program) was dissolved in 0.9% saline and filter sterilized. Nicotine doses were based on salt. OT (Spectrum Chemicals, New Brunswick, NJ) was dissolved in 10 ml of 0.9% saline to make 160 IU/ml stock solution. OT stock solutions were diluted with saline to 2 ml for each dose. We used IV OT, as intranasal administration in baboons is not practical and a recent study in nonhuman primates demonstrated central nervous system penetrance of IV administered OT (80 IU), and comparable pharmacokinetics and concentrations in cerebral spinal fluid of IV and intranasal routes [33].

Experiment 1: single access alcohol availability

Experimental sessions were conducted seven days per week and began at the same time each day. A 4% w/v alcohol concentration was selected for self-administration based on our prior studies in baboons with alcohol drinking experience [34, 35]. Alcohol (4% w/v) was available under an FR3 schedule of reinforcement on the alcohol lever for each “drink”. Alcohol availability was signaled by a 5-s tone, followed by illumination of the jewel light above the alcohol lever. Completion of the FR3 turned off the jewel light and illuminated of the green lights on the drink-o-meter (signaling drink availability); contact with the drink spout activated the drink-o-meter and fluid flowed for 5 s or until spout contact was broken, whichever occurred first. This defined a single “drink” of alcohol (typically ~35 ml). A 30-s timeout, correlated with illumination of the bay light, began after the FR3 was completed. During timeout, responses were recorded but had no programmed consequence. A minimum of 10 sessions were conducted and sessions continued until self-administration was stable based on criteria as detailed below.

Oxytocin test procedures

After self-administration was stable (total intake was within ±20% for 3 consecutive sessions), (20–120 IU) or its vehicle (saline) was injected via the intravenous catheter twice daily (i.e., total dose of 40–240 IU), for five consecutive days. Filter sterilized OT doses were slowly injected into the catheter over 2 min, followed by a 5-ml saline flush. Vehicle (saline) was administered using the same volume and route of injection.

The first injection of OT or vehicle was administered 15 min before the 6-h session, and the second injection of OT or vehicle was administered 3 h later (i.e., during the middle of the session). Baseline levels of intake were re-established for at least 1 week and stability criteria met during a washout period before proceeding to the next dosing period. OT doses were selected based on doses tested in humans and our prior primate research demonstrating brain penetrance of IV OT [33].

Experiment 2: alcohol and nicotine concurrent-access (ANCA)

Three of the baboons from Experiment 1 completed Experiment 2; two baboons did not complete Experiment 2 due to issues unrelated to OT administration. The session duration (6-h) and frequency (7 days/week) and start time for Experiment 2 sessions were the same as those for Experiment 1, but in Experiment 2, both alcohol (4% w/v) and nicotine (0.056 mg/kg/infusion) were available for self-administration under the ANCA procedure. Nicotine infusions (0.056 mg/kg/infusion) were available under an FR3 schedule of reinforcement on the nicotine lever. The 0.056 mg/kg nicotine dose produced reliable self-administration in our prior study [29]. In addition, the average total intake for 0.056 mg/kg nicotine exceeded the total nicotine content of 10 tobacco cigarettes. In humans, smoking a single standard cigarette delivers about 1 mg nicotine, and regularly smoking 10 cigarettes per day or more is strongly associated with nicotine dependence [36]. In the ANCA procedures, nicotine injection availability was signaled by a 5-s tone, followed by illumination of the cue light above the nicotine lever. Completion of the FR3 turned off the cue light and an IV infusion of nicotine was delivered over 50 s followed by a 0.9% saline flush infusion over 50 s during which the bay light was illuminated. This was then followed by a 30-s timeout. During timeout, responses were recorded but had no programmed consequence. Drinks of alcohol were available under an FR3 schedule of reinforcement on the alcohol lever and nicotine injections were available under an FR3 schedule of reinforcement on the nicotine lever. Responses on the lever for one drug did not affect access to or delivery of the other drug.

Behavioral observations in Experiments 1 and 2

Behavioral observations were made for 10 min each day immediately following the first OT/vehicle administration of the day, prior to the start of the self-administration session. The observers were not blind to the condition in effect. Behavioral observations did not occur on baseline days. Veterinary technicians completed daily behavioral observations in real-time. Trained observers sat in a chair in front of the cage with a standardized paper checklist and recorded the presence or absence (1 or 0, respectively) of behaviors in 10 consecutive 1-minute bins during the 10-min behavioral observation period. Baboons were habituated to the presence of observer prior to experiments. Behavioral data were categorized into social/aggressive (“aggressive” or “yawn”), self-directed (“nose rub/wipe” or “scratch/groom”), withdrawal (“brux” or “wet dog shake” or “withdrawn posture”), ataxia/sedation (“ataxia” or “lip droop”), nausea/vomit (“vomit or gag/retch” or “head below torso posture”), pre-convulsant (“limb or body tremor/jerk” or “rigidly braced”), and resting postures (“laying down posture” or “resting (eyes closed)”). Frequencies per category (maximum frequency = 10 per category/session) were then averaged across the 5 days of treatment. If a baboon did not consume its standard amount of daily chow following an OT/Vehicle treatment day, this was recorded as a “1” (vs. “0” for all food eaten).

Data analysis

Alcohol (g/kg) and nicotine (mg/kg) intake are each defined as the total dose during each session based on the most recent body weight for each animal. Total water intake (24 h) was recorded daily at the same time each day in milliliters. The mean intake of alcohol and nicotine over the washout session before each dosing period of OT/vehicle was used as the baseline.

The effects of OT on alcohol consumption and number of responses (% change from baseline) (Experiment 1) were each analyzed using a mixed effects model (MEM) with OT DOSE (vehicle, 20, 40, 80, 120 IU) and DAY (1, 2, 3, 4, 5) as repeated measures as well as SUBJECT as a random factor. To evaluate any baseline changes in alcohol intake across the experimental timeline, alcohol consumption during the 5 baseline sessions preceding each OT/vehicle session, as well as the vehicle sessions paired with each OT administration, were also examined with a MEM with DAY and DOSE as repeated measures, SUBJECT as random factor. Baseline and vehicle session alcohol consumption was compared with a paired t-test. Total daily water consumption (ml over 24 h) was tabulated and entered into a MEM with OT DOSE and DAY as repeated measures and SUBJECT as random factor. A p-value of .05 or less was considered significant. Planned post-hoc comparisons were conducted for significant effects of MEM between vehicle and each OT DOSE and multiple testing was Bonferroni corrected (p ≤ 0.0125). Behavioral observations were tested for normality using the Shapiro-Wilk test. As most categories were non-normally distributed, Friedman tests were used determine OT dose effects on frequencies of behavior by category, followed by post-hoc testing within each dose compared with vehicle using Wilcoxon signed rank testing. Statistical analyses were conducted using SPSS.

This study used a within-subjects design, where each subject is exposed to multiple experimental conditions and baseline criteria is met prior to drug treatments, which requires fewer subjects than conventional group designs to draw statistically significant, meaningful conclusions. Use of a within-subjects research design is consistent with the recommendations of the National Institutes of Health National Primate Plan and the restrictions of the Animal Welfare Act, to fully utilize each subject and minimize the number of nonhuman primates used in research. The number of subjects used in the present study (N = 5) was sufficient based on results of other non-human primate studies using similar approaches and estimated effect size based on our earlier work [25, 27–29, 37, 38].

For the ANCA study (Experiment 2), N = 3 baboons, exploratory data are shown for each subject where each baboon served as his own control. The primary data are the mean nicotine (mg/kg) and alcohol (g/kg) intake across the 5 treatment days for each baboon and are shown in Fig. 2 for alcohol and nicotine by OT dose. The baseline data are presented as the mean of all 5-day periods that preceded each OT/vehicle treatment.

Results

Experiment 1

There was a significant main effect of OT DOSE on alcohol consumption (% change from baseline), F (4, 26.35) = 4.06, p = 0.011. There was no significant main effect of DAY, F (4, 36.29) = 0.50, p = 0.733, and no significant DAY × DOSE interaction, F (16, 17.50) = 0.337, p = 0.983. Planned post-hoc comparison of each OT dose to vehicle revealed that there was a significant reduction in alcohol consumption between vehicle and each dose of OT (vehicle vs. 20 IU: p = 0.034, 40 IU: p = 0.005, 80 IU: p = 0.018, 120 IU: p = 0.035, uncorrected). Correcting for multiple comparisons, the 40 IU and 80 IU doses were significantly different from vehicle (p < 0.0125; Fig. 1A).Fig. 1 Experiment 1: Effects of chronic (5 day) administration of vehicle (0 IU) or oxytocin (20, 40, 80, 120 IU) BID.

A. % of baseline alcohol (4% w/v) consumed over 6 h per day. B. % of baseline responses during the session. Data shown are means (+SD) averaged over each 5-day session for N = 5 baboons. *indicates a significant difference compared to vehicle (p < 0.0125, Bonferroni corrected).

There was a significant main effect of OT DOSE on responses (% change from baseline), F (4, 26.68) = 6.69, p = 0.001. There was no significant main effect of DAY, F (4, 36.19) = 0.75, p = 0.568. There was no significant DAY × DOSE interaction, F (16, 21.55) = 0.537, p = 0.896. Planned post-hoc comparison of each OT dose to vehicle revealed that there was a significant reduction in responses between vehicle and each dose of OT (vehicle vs. 20 IU: p = 0.015, 40 IU: p < 0.001, 80 IU: p = 0.020, 120 IU: p = 0.052, uncorrected). Correcting for multiple comparisons, the 40 IU dose of OT was significantly different from vehicle (p < 0.0125; Fig. 1B). Cumulative responses for each dose of OT/vehicle over the 6-h access session collapsed over the 5-day administration period (as there was no main effect of DAY or DAY × DOSE interaction) are shown in Fig. 2.Fig. 2 Experiment 1: Cumulative responses over the 6-h alcohol administration session for each dose of oxytocin (OT) and vehicle.

Data shown are means (±SD) collapsed over the 5 days of administration of each OT/vehicle dose. Arrows indicate the time point of OT administration.

MEMs for vehicle and baseline alcohol consumption revealed no significant main effect of DAY or DOSE, nor DAY × DOSE interaction for any vehicle or baseline sessions. Paired-t-test comparison of baseline and vehicle alcohol consumption was not significant (p = 0.344). MEM for daily water consumption also revealed no significant main effect of DAY or DOSE, nor DAY × DOSE interaction. Average ± SEM intake of water for the different dose conditions were 774.6 ± 142.3 mL (Vehicle), 696.0 ± 102.8 mL (20 OT), 746.0 ± 109.1 mL (40 OT), 800.0 ± 156.8 mL (80 OT), and 744.0 ± 188.2 mL (120 OT).

Experiment 2: ANCA

The effects of OT on alcohol and nicotine consumption in the ANCA procedure are shown in Fig. 3. An effect of OT on nicotine or alcohol intake was concluded if the standard deviation for the test dose did not overlap with those for the baseline and vehicle condition (i.e., non-overlapping error bars in Fig. 3, denoted by +). At least one OT dose reduced nicotine consumption and/or alcohol consumption in two of three baboons tested.Fig. 3 Experiment 2: Total nicotine intake and total alcohol consumed during baseline (BL), Vehicle (Veh), 20, 40, 80, 120 IU oxytocin (OT) BID sessions for each baboon (n = 3).

Data shown are the means (+SD) of the 5-day alcohol consumed (g/kg, 4% w/v alcohol) and nicotine intake (mg/kg; 0.056 mg/kg/injection) during concurrent self-administration (ANCA) sessions for each OT/veh dose. The baseline data are presented as the mean of all 5-day periods that preceded each OT/veh treatment. Test doses that had an SD that did not overlap with baseline and vehicle SD are denoted by +.

Behavioral observations

A 5-day average of frequencies of observed behaviors (0–10) and decreased food intake (0–1) during OT administration compared with vehicle administration are shown in Table 2 (Experiment 1) and Table 3 (Experiment 2). Due to low frequencies of any observed behaviors for ataxia/sedation and pre-convulsant categories (mean < 1 for each baboon, under each condition), these data are not shown.Table 2 Average frequencies of observed behaviors in Experiment 1 (alcohol alone).

	ID	Social/aggressive	Self-directed	Withdrawal	Nausea/vomit	Laying/resting	Not all food consumed	
Vehicle	BV	1.05	5.55	0.45	0.00	0.00	0.00	
BS	3.33	4.50	0.55	0.00	0.80	0.00	
CY	1.65	5.10	0.85	1.25	0.05	0.00	
GG	1.88	4.78	0.45	0.20	0.45	0.00	
SK	1.65	3.85	0.65	0.55	0.20	0.00	
AVG	1.91	4.76	0.59	0.40	0.30	0.00	
20 IUs Oxytocin	BV	0.00	3.00	0.00	0.40	5.00	0.00	
BS	2.20	3.50	0.70	0.00	1.30	0.00	
CY	0.80	4.00	1.20	2.60	0.00	0.00	
GG	1.75	3.00	0.25	0.50	3.00	0.00	
SK	1.20	5.40	0.80	0.20	2.80	0.00	
AVG	1.19	3.78	0.59	0.74	2.42	0.00	
40 IUs Oxytocin	BV	0.20	3.00	0.20	0.00	5.00	0.00	
BS	1.80	4.60	0.50	0.00	2.90	0.00	
CY	1.20	3.60	0.40	0.40	3.40	0.00	
GG	0.20	3.70	0.40	0.10	2.80	0.00	
SK	1.60	5.20	0.80	1.00	2.60	0.00	
AVG	1.00	4.02	0.46	0.30	3.34	0.00	
80 IUs Oxytocin	BV	0.80	3.00	0.00	0.00	5.80	0.20	
BS	2.75	4.00	0.75	0.00	1.00	0.00	
CY	1.60	2.40	0.40	3.00	0.00	0.00	
GG	0.80	4.60	0.60	0.00	2.00	0.00	
SK	1.00	4.20	0.40	0.60	3.80	0.00	
AVG	1.39	3.64	0.43	0.72	2.52	0.04	
120 IUs Oxytocin	BV	0.00	2.80	0.00	0.00	6.40	1.00	
BS	1.00	3.40	0.40	0.80	6.80	0.00	
CY	0.40	3.00	0.60	1.60	2.40	0.40	
GG	1.00	3.00	0.80	0.00	4.00	0.00	
SK	0.20	3.60	0.40	0.00	1.80	0.00	
AVG	0.52	3.16	0.44	0.48	4.28	0.28	
Friedman Test	Chi-Sq	13.212	9.979	1.677	1.873	8.694	7.077	
p-value	0.010a	0.041a	0.795	0.759	0.069	0.132	
An asterisk aindicates a significant effect of OT dose on behavior in the Friedman’s test. Average values for the group are in bold text.

Table 3 Average frequencies of observed behaviors in Experiment 2 (ANCA).

	ID	Social/aggressive	Self-directed	Withdrawal	Nausea/vomit	Laying/resting	Not all food consumed	
Vehicle	CY	0.80	3.10	0.65	2.05	0.00	0.00	
GG	1.95	4.60	0.70	0.65	0.15	0.00	
SK	1.40	3.33	0.73	0.73	0.00	0.00	
AVG	1.38	3.68	0.69	1.14	0.05	0.00	
20 IU Oxytocin	CY	0.60	4.00	0.80	0.60	0.80	0.00	
GG	1.40	2.70	0.40	0.20	3.00	0.20	
SK	0.20	4.40	0.80	0.00	0.00	0.00	
AVG	0.73	3.70	0.67	0.27	1.27	0.07	
40 IU Oxytocin	CY	0.40	3.40	0.00	2.80	1.80	0.00	
GG	0.60	2.80	0.40	0.00	6.40	0.00	
SK	0.80	4.40	1.00	0.80	0.60	0.00	
AVG	0.60	3.53	0.47	1.20	2.93	0.00	
80 IU Oxytocin	CY	0.00	2.40	1.00	1.00	1.20	0.00	
GG	0.00	1.40	0.40	0.00	9.20	0.00	
SK	0.00	3.60	0.40	0.00	3.60	0.00	
AVG	0.00	2.47	0.60	0.33	4.67	0.00	
120 IU Oxytocin	CY	0.20	1.40	0.40	0.60	1.40	0.80	
GG	0.00	1.20	0.20	0.00	9.00	0.60	
SK	0.80	3.80	1.00	0.20	1.80	0.00	
AVG	0.33	2.13	0.53	0.27	4.07	0.47	
Friedman Test	Chi-Sq	9.862	6.712	0.655	6.148	9.695	7.077	
p-value	0.043a	0.152	0.957	0.188	0.046a	0.132	
An asterisk aindicates a significant effect of OT dose on behavior in the Friedman’s test. Average values for the group are in bold text.

Friedman testing indicated a significant effect of OT DOSE on social-aggressive behavior in Experiment 1 (p = 0.01). Wilcoxon signed-rank post-hoc tests indicated that social-aggressive behavior was lower under all OT dose conditions compared with Vehicle (p’s = 0.043), however this does not pass significance testing after Bonferroni correction (i.e., p < 0.0125). There was a significant effect of OT DOSE on self-directed behaviors (p = 0.041) in the Friedman test, with Wilcoxon-ranked post-hoc test indicating 120 IU reduced the frequency of self-directed behaviors compared with vehicle (p = 0.043), though this was not significant following Bonferroni correction. In Experiment 2 (ANCA), there was also a significant effect of OT DOSE on social-aggressive behavior (p = 0.04), though no OT dose was significantly different from vehicle in post-hoc tests. There was also a significant effect of OT dose on Laying/Resting in Experiment 2, though no OT dose was significantly different from vehicle in post-hoc tests.

Discussion

The present study evaluated the effects of OT in nonhuman primates under a 6-h extended access procedure when alcohol was the only drug available (single access) and when both alcohol and nicotine were available (concurrent access). This is the first study testing the effect of OT on alcohol self-administration and alcohol/nicotine coadministration in nonhuman primates.

First, administration of OT compared to vehicle significantly reduced alcohol intake by 10–12% (change from baseline) at the 40 and 80 IU BID doses of OT. Of note, these are the doses which have been shown to result in brain penetrance in nonhuman primates [33, 39], and are in the range of those used in a large multisite randomized controlled clinical trial examining OT as a treatment for AUD (NCT03878316) i.e., 35 IU intranasal OT BID. Likewise, self-administration responses (change from baseline) were significantly decreased at the 40 IU OT dose, compared to vehicle during the 6-h access sessions over 5 days. Of note, the quantity of water and food consumed over each 24-h period did not change as a consequence of OT administration compared to vehicle. Lastly, the absence of a main effect of DAY or a DRUG × DAY interaction indicates that this was not a transient reduction in alcohol consumption or responding but this effect persisted over the 5-day dosing period.

Behavioral data from observations immediately after the first dose of OT/vehicle are in Tables 2 and 3. These data indicate that there was a small reduction in social/aggressive and self-directed behaviors and an increase in laying/resting behaviors in the OT treatment conditions. These changes were not just observed in the doses that significantly reduced self-administration of alcohol. OT when given systemically to nonhuman primates has been reported to be a mild sedative [40] and has well known effects on prosocial behavior [41]. Behavioral data for the period after the second intravenous OT dose of the day during the self-administration session was not collected. Water and food intake did not change because of OT administration, though this was only evaluated across the 24-h period. Therefore, this indicates a specific effect of BID IV OT on alcohol consumption in a 6-h extended alcohol access procedure in nonhuman primates. This procedure produced stable day-to-day alcohol intake and thus allowed detection of changes in behavior and alcohol intake, while modeling key characteristics of human ‘at risk’ heavy drinking. Of interest is the effect of OT on the pattern of responding during this 6-h alcohol access session. Importantly, the effect of OT on responding appears to be most apparent after the second dose administration (Fig. 2). This may reflect a dose effect which will be important to examine in the human randomized clinical trial administering comparable intranasal doses of OT BID.

The mechanism by which systemically administered OT reduces alcohol intake is unclear. In human post-mortem studies of individuals with AUD compared to those without AUD, there is a loss of OT immunoreactivity in the hypothalamus [42] with upregulation of OT receptor in frontal and striatal areas [9]. Further, administration of intranasal OT to male heavy drinkers reduced neural response to alcohol cue exposure in regions found to exhibit upregulated OT receptor expression in human and rodent post-mortem studies [9]. In a recent case-control, postmortem brain proteomics study [43], the OT signaling pathway was found to be enriched and predicted to be the most activated pathway in the amygdala in individuals with AUD. Taken together, there seems to be a loss of central oxytocin function and these reported brain changes appear to be a compensatory mechanism. Therefore, it is hypothesized that administering OT may remediate an OT signaling deficiency in AUD. Nevertheless, the mechanism underlying how OT administration reduces alcohol consumption or if the administration of OT reverses the loss of central OT function is unknown. Centrally administered OT reduced ethanol consumption and ethanol-induced dopamine release in the nucleus accumbens of rats [44]. From rodent studies, we know that the effect of intranasal OT on reducing alcohol self-administration in an alcohol dependent rodent model is centrally mediated [10] and the doses that produced a statistically significant effect (corrected) in this study are those that have been shown to achieve central nervous system penetrance when administered IV [33]. The model employed here is particularly relevant given these human post-mortem studies, as the animals were experienced alcohol drinkers that consumed significant amounts of alcohol (e.g., 1–2 g/kg per day) seven days a week. Therefore, the molecular changes reported in human post-mortem studies may also translate to these nonhuman primates.

The effects reported here of IV OT on nicotine self-administration concurrent with alcohol self-administration are exploratory. We found that in each of 3 animals at least one dose of OT reduced the quantity of nicotine self-administration by 1 standard deviation when co-administered with alcohol. Of note, the 3 subjects that completed Experiment 2 had variable amounts of alcohol and nicotine co-self-administration experience (CY: 0.5 months, SK: 6 months, GG: 1.3 years) prior to OT administration, which may underlie differential response. However, this effect of OT should be examined further as the central OT system has also been found to be altered in nicotine addiction [45] and given the comorbidity of alcohol and nicotine addiction, OT may have promise as a parsimonious treatment for the comorbid disorders.

This nonhuman primate study has several other limitations and results should be considered preliminary. This is the first report of the effect of a drug treatment using the 6-h alcohol single access condition. Our previous studies employing a 2-h CSR procedure have shown reductions in drinking with treatments including naltrexone, baclofen and varenicline. We also previously demonstrated an effect of varenicline on reducing alcohol and nicotine intake in the 6-h alcohol and nicotine concurrent access (ANCA) model [29] but varenicline was not evaluated under 6-h alcohol single access conditions. The 6-h alcohol access condition reflects excessive drinking patterns in quantity and duration seen in some people with AUD and therefore we believe that this is a useful translational model that should be validated further. Further, this study was completed in male baboons only, not allowing for determination of sex differences in OT effects in the current study. According to the NIH, one of the allowable justifications for single sex studies is the use of NHP, which are a scarce resource. Further examination of sex is warranted, as sex differences have been observed in the OT system at baseline and following alcohol consumption [46], as well as effects of OT system activation on alcohol intake [47].

Further studies should examine OT as a potential therapeutic to reduce alcohol consumption and explore dose effects for other alcohol -related behaviors and with chronic oxytocin dosing. Overall, this translational study provides evidence that systemic OT can reduce alcohol administration in a nonhuman primate animal who are experienced in alcohol administration during drinking sessions that approximate those of humans in quantity and duration.

Acknowledgements

This research was supported by NIH NIAAA R01AA015971 (EW) and Bench-to-Bedside (B2B) Grant (ML) funded by the NIH Office of Behavioral and Social Sciences Research (OBSSR).

Author contributions

EW and ML conceptualized the study. EW designed the study and secured project funding. EW and CM performed the experiments. ML and CM analyzed the data. ML wrote the original paper draft. All authors contributed to data interpretation, editing, and paper review.

Data availability

All data associated with this study are available upon request.

Competing interests

Dr. Lee, Dr. Weerts and Dr. Moore do not have any competing financial interests in relation to the work described.

Ethics approval and consent to participate

The experimental protocol was approved by the Johns Hopkins University Animal Care and Use Committee. Facilities were maintained in accordance with USDA and AALAC standards and followed the Guide for the Care and Use of Laboratory Animals (2010).

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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