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Published in final edited form as: Behav Brain Res. 2024 Jan 24;462:114881. doi: 10.1016/j.bbr.2024.114881

Sex-dependent regulation of social avoidance by oxytocin signaling in the ventral tegmental area

Zachary A Grieb 1, Susan Lee 1, Maura C Stoehr 1, Benjamin W Horne 1, Alisa Norvelle 1, Emma K Shaughnessy 1, H Elliott Albers 1, Kim L Huhman 1,*
PMCID: PMC10923107  NIHMSID: NIHMS1964659  PMID: 38272188

Abstract

It has been hypothesized that oxytocin increases the salience of social stimuli, whether the valence is positive or negative, through its interactions with the ventral tegmental area (VTA). Indeed, oxytocin neurons project to the VTA and activate dopamine neurons that are necessary for social experiences with positive valence. Surprisingly, though, there has not been an investigation of the role of oxytocin in the VTA in mediating social experiences with negative valence (e.g., social stress). Given that there are sex differences in how oxytocin regulates the salience of positively-valenced social interactions, we hypothesized that oxytocin acting in the VTA also alters the salience of social stress in a sex-dependent manner. To test this, female and male Syrian hamsters were site-specifically infused with either saline, oxytocin (9 μM), or oxytocin receptor antagonist (90 μM) into the VTA. Subjects were then exposed to either no defeat or a single, 15 min defeat by one RA. The day following social defeat, subjects underwent a 5 min social avoidance test. There was an interaction between sex and drug treatment, such that the oxytocin antagonist increased social avoidance compared to saline treatment in socially stressed females, while oxytocin decreased social avoidance compared to saline treatment in socially stressed males. Contrary to expectations, these results suggest that oxytocin signaling generally acts to decrease social avoidance, regardless of sex. These sex differences in the efficacy of oxytocin and oxytocin receptor antagonists to alter negatively-valenced social stimuli, however, should be considered when guiding pharmacotherapies for disorders involving social deficits.

Keywords: Oxytocin, ventral tegmental area, social stress, social defeat, avoidance

1. Introduction

Oxytocin has long been studied for its ability to enhance the salience of positive social interactions [1–3]. However, oxytocin can also have antisocial effects, increasing envy, schadenfreude, and relational distress in humans [4–7]. These contrasting effects have led to the hypothesis that oxytocin increases the salience of social stimuli, whether the valence is positive or negative, through its interactions with the mesolimbic dopamine system [8]. The mesolimbic dopamine system is defined by the dopaminergic ventral tegmental area (VTA) projections to the nucleus accumbens [9]. Paraventricular nucleus neurons containing oxytocin project to the VTA and activate dopamine neurons [10, 11]. This dopaminergic activation is necessary for social experiences to have a positive valence, such as the social reward experienced during non-agonistic social encounters [10–14]. Surprisingly, though, there has yet to be an investigation of the role of oxytocin in the VTA in mediating social experiences with negative valence.

Negatively-valanced social experiences are a considerable risk factor for neuropsychiatric disorders [15], such as depression [16, 17] and anxiety disorders [18]. Social stressors are also the most common stressors experienced by humans [19, 20]. Therefore, social defeat models are widely used to investigate the underlying mechanisms/behavioral consequences of social stress and ultimately human psychopathology [15, 21, 22]. As we have discussed in detail before [15], Syrian hamsters are ideal subjects with which to study the effects of social stress because unlike most other commonly used laboratory rodents, both male and female hamsters spontaneously exhibit very similar agonistic behaviors in the lab and both sexes respond to social defeat with social avoidance. This allows us to directly compare the effects of pharmacological and behavioral manipulations in male and female hamsters. In addition, these responses occur following a single exposure to social defeat making it possible to study the effects of mild social stress in the absence of tissue damage [15].

Disorders associated with dysfunctional stress reactivity, such as PTSD [20], depression [23], and anxiety disorders [23, 24], are also associated with enhanced salience of and attention to negatively-valenced social stimuli. Interestingly, though, there is evidence that females and males have different “dose response curves” to social stimuli [12, 13, 25–28], which results in oxytocin acting in the VTA decreasing the salience of positively-valenced social stimuli in females while increasing the salience of positively-valenced social stimuli in males. This suggests that oxytocin might have different effects on the salience to social defeat based on sex. Therefore, we tested the hypothesis that oxytocin signaling in the VTA regulates the salience of social stress in a sex-dependent manner.

2. Methods

2.1. Subjects

Adult female and male Syrian hamsters (N = 103) were obtained from Charles River Laboratories (Wilmington, MA) at approximately 2 months of age and weighing between 120g and 130g. After recovery from shipping, animals were individually housed for 4 days before surgery (see description under Stereotaxic surgery) in 24cm X 33cm X 20cm polycarbonate cages filled with corncob bedding and nesting material. Food and water were available ad libitum. It is important to note that single housing does not appear to be stressful for Syrian hamsters [29]. Following surgery, females’ cycles were monitored for eight days to confirm regular cyclicity, with males handled similarly each day. In addition to our female and male test subjects, female and male resident aggressors (RAs) were also used for social defeat training as described in detail below. RAs were larger, individually-housed Syrian hamsters, and female RAs were ovariectomized to avoid estrous cycle-induced variation in aggressive behavior [30]. All drug infusions and behavioral testing occurred under red light during the first 3 hr. of the dark phase of the daily cycle to minimize circadian variation in behavior and because this is the phase of the light-dark cycle when hamsters are normally active. All procedures and protocols were performed in accordance with the principles of the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee at Georgia State University.

2.2. Stereotaxic surgery

On the day of surgery, subjects were anesthetized with isoflurane (induced at 5% and maintained at 2–4%), and a 4 mm 26-guage cannula was implanted unilaterally and aimed at the ventral tegmental area (VTA; from bregma: anteroposterior −3.80 mm; mediolateral +0.55 mm; dorsoventral −3.20 mm; 0° angle). Guide cannulae were secured to the skull with screws and dental adhesive. Dummy caps were inserted into the cannula guides to prevent clogging. Following surgery, subjects were injected subcutaneously with the anti-inflammatory drug, ketofen (5 mg/kg), and then again 24 hrs later. Subjects were allowed to recover for at least 8 days before social defeat training.

2.3. Drug microinjections

Following surgical recovery and on either Diestrus 1 or Diestrus 2, females and yoked males were taken to the behavioral testing suite. Once there, microinjections were administered using a 12 mm, 32-gauge needle attached to a 1 uL Hamilton syringe. The fine gauge injection needle extended an additional 4.2 mm beyond the cannula guide to a final depth of 7.4 mm below the skull surface (i.e., targeting the VTA to minimize tissue damage caused by the injection procedure). The drugs used were oxytocin (Bachem, CA) dissolved in sterile saline to a final concentration of 9 μM and desGly-NH2-d(CH2)5[D-Tyr2,Thr4]OVT, a highly selective oxytocin receptor antagonist (Manning et al., 2012) (gift from Maurice Manning) dissolved in sterile saline at a final concentration of 90 μM. Concentrations of oxytocin and oxytocin antagonist were chosen based on previous work showing the efficacy of those doses to affect social behaviors in Syrian hamsters [12, 14, 31]. 200 nL of saline or drug was infused into the VTA at a rate of 400 nL/min and allowed to diffuse for 30 sec before the needle was removed. Following infusion, the dummy caps were replaced, and subjects underwent immediate social defeat training.

2.4. Social defeat training and avoidance testing

To test the effects of oxytocin manipulations in the VTA on the salience to social stress, we used a social defeat procedure previously employed [21, 27, 32]. Briefly, following microinjections, the subjects in the no stress group (i.e., no defeat controls) were placed into the empty cage of a same-sex RA for one, 15 min session. This group controlled for the effects of variables except social defeat (i.e., handling, novel cage exposure, odors of an aggressive conspecific). For the social stress group, we placed subjects into the cage of a same-sex RA for 15 min after the first aggressive posture was exhibited by the RA. After 15 min, subjects were returned to their home cages. To ensure that any effects observed were due to drugs affecting the salience of the defeat, and not due to alteration of the defeat, itself, behavior of RAs and subjects during defeat training was also scored. The day following defeat, the no defeat controls, and defeated subjects were placed for 5 min into a novel, clean cage facing away from an unfamiliar RA that was confined in a plastic mesh cage (13.5cm × 13.5cm × 7cm) that allowed the test subjects to smell, hear, and see the RA without allowing any direct contact between the animals. We measured social avoidance, social vigilance, and social investigation of the subjects. Operational definitions of these behaviors can be found in [27]. All behaviors were videorecorded and later analyzed using the Noldus Observer system (11.5, Leesburg, VA). Experimenters that were blind to the treatment groups scored each recording. To minimize potential effects of estrous cyclicity in females, hamsters were defeated on Diestrus 1 (D1) or 2 (D2) and social avoidance was tested on Diestrus 2 or Proestrus (P). Defeated females are also more likely to produce submissive or avoidant responses on D2 and P [30].

2.5. Confirmation of injection site

To ensure site-specific infusion of saline or drug into the VTA, following avoidance testing subjects were euthanized with a lethal dose of sodium pentobarbital (0.2 ml, intraperitoneally, Henry Schein Animal Health, Dublin, Ohio) and 200 nL of India ink was microinjected through the guide cannula to mark the injection site. Brains were then extracted and sectioned coronally using a cryostat (Leica). An accurate injection into the VTA was confirmed if the VTA, but not the surrounding areas, contained India ink. Seven subjects across groups were deemed misses and were excluded from statistical analysis.

2.6. Statistical analysis

Data were analyzed using SPSS version 28 (IBM). A 2×3×2 between-subjects analysis of variance (ANOVA) was run with sex, drug treatment, and defeat condition as the factors, respectively. In cases of statistical significance, Fisher’s Least Significant Difference (LSD) post-hoc tests were used to examine group differences. Main effects were reported if they were informative above and beyond interaction effects. Partial η2 (η2p) are reported as measures of effect sizes from the ANOVAs and Cohen’s d are reported as measures of effect sizes for post-hoc analyses. All data are presented as means ± standard error of the mean. Statistical significance was conferred at p < 0.05.

3. Results

3.1. Effects of sex, drug treatment, and defeat condition on social avoidance

There was a significant interaction between sex and drug treatment on social avoidance (F (2, 93) = 3.50, p = 0.03, η2p = 0.07; Figure 1), such that oxytocin antagonist treatment increased social avoidance compared to saline treatment in defeated females (p < 0.05; d = 1.60), while oxytocin treatment decreased social avoidance compared to saline treatment in defeated males (p < 0.05; d = 1.12). There was also a main effect of defeat condition on social avoidance (F (1, 93) = 24.54, p < 0.01, η2p = 0.21; Figure 1), such that defeated subjects avoided more than did non-defeated subjects.

Figure 1: Social avoidance is regulated by oxytocin signaling in the ventral tegmental area in a sex-dependent manner.

Figure 1:

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Duration expressed as Mean ± SEM of social avoidance operationally defined as time on the far side of the cage by saline-treated, oxytocin-treated (OT), or oxytocin antagonist-treated (OTA) female and male Syrian hamsters that were not socially defeated (No defeat) or that were defeated one time for 15 minutes (Defeat). Dots represent one data point and group n’s are shown by the number inside bars. Different letters above bars indicate significant differences among groups, p < 0.05. * indicates a significant effect of defeat, p < 0.05.

3.2. Effects of sex, drug treatment, and defeat condition on social vigilance

There was a main effect of defeat condition on social vigilance (F (1, 93) = 7.95, p < 0.01, η2p = 0.08; Figure 2), such that defeated subjects were more socially vigilant than were non-defeated subjects. There were no interactions among sex, drug treatment, or defeat conditions nor were there main effects of sex or drug on social vigilance (p’s > 0.05).

Figure 2. Social defeat increases social vigilance regardless of sex and drug treatment.

Figure 2.

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Duration expressed as Mean ± SEM of social vigilance operationally defined as time standing on their back legs with head oriented towards the caged RA or time being in a frozen stretch attend position with their head oriented towards the caged RA by saline-treated, oxytocin-treated (OT), or oxytocin antagonist-treated (OTA), male and female Syrian hamsters that were not socially defeated (No defeat) or that were defeated one time for 15 minutes (Defeat). Note: There was no effect of sex or drug on social vigilance. Dots represent one data point and group n’s are shown by the number on top of the bars. * indicates a significant effect of defeat, p < 0.05.

3.3. Effects of sex, drug treatment, and defeat condition on social investigation

There was a main effect of defeat condition on social investigation (F (1, 93) = 97.77, p < 0.01, η2p = 0.51; Figure 3), such that defeated subjects investigated the caged opponent less than did non-defeated subjects. There were no interactions between sex, drug treatment, or defeat conditions nor were there main effects of sex or drug on social vigilance (p’s > 0.05).

Figure 3. Social defeat decreases social investigation regardless of sex and drug treatment.

Figure 3.

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Duration expressed as Mean ± SEM of social investigation operationally defined as time the subjects’ nose contacted the mesh cage housing a confined resident aggressor by saline-treated, oxytocin-treated (OT), and oxytocin antagonist-treated (OTA), male and female Syrian hamsters that were not socially defeated (No defeat) or that were defeated one time for 15 minutes (Defeat). Note: There was no effect of sex or drug on social vigilance. Dots represent one data point and group n’s are shown by the number inside bars. All values are expressed as Mean ± SEM. * indicates a significant effect of defeat, p < 0.05.

3.4. Effects of sex and drug treatment on behavior of Resident Aggressors and opponents during social defeat training

The behavior of hamsters (both aggressors and their opponents) during defeat training was randomly scored for approximately 75% of the pairings. In resident aggressors, there was no significant interaction of drug and sex on aggression (F (2, 35) = 0.28, p = 0.76) and no significant main effect of either sex (F (1, 35) = 2.83, p = 0.10) or drug (F (2, 35) = 0.79, p = 0.46), indicating that drug received by the opponents before social defeat training did not alter the behavior of the RAs toward their opponent. In defeated hamsters, there was no significant interaction of drug and sex on submissive behavior emitted during defeat training (F (2, 35) = 1.38, p = 0.27) and no significant main effect of either sex (F (1, 35) = 0.27, p = 0.60) or drug (F (2, 35) = 0.45, p = 0.64), indicating that drug status did not significantly alter the response of hamsters during social defeat training.

4. Discussion

Here, we tested the hypothesis that oxytocin signaling in the VTA regulates the salience of a negatively-valenced social experience, namely social defeat and that it does so in a sex-dependent manner. The data support the hypothesis that oxytocin signaling in the VTA plays a role in modulating behavioral responses to social defeat stress. Contrary to our hypothesis, however, and to our previous data that oxytocin signaling has opposite effects in males and females on behavioral responses to prosocial, or positively-valenced, stimuli, we found that oxytocin signaling appears to act in a similar manner in female and male Syrian hamsters to decrease social avoidance after a previous social defeat. Specifically, the oxytocin antagonist increased social avoidance in defeated females compared to that observed in saline-treated, defeated controls, while oxytocin, itself, decreased social avoidance in defeated males compared to their saline-treated, defeated controls (Fig. 1). The interaction between sex and drug treatment in this study might be driven by natural differences between female and male Syrian hamsters in their susceptibility to social stress. For example, saline-treated, defeated females displayed less social avoidance than did saline-treated, defeated males (Fig. 1; p < 0.05), which is consistent with previous work showing that males are often more susceptible to losing agonistic encounters than are females [21, 27, 33, 34].

The present data expand on previous data to suggest that sex differences in the susceptibility of social stress might be mediated, in part, by basal sex differences in oxytocin acting in the VTA [21, 27, 33, 34]. Thus, it is possible that females might have higher oxytocin signaling during defeat that would then act to protect females from the effects of social defeat (i.e., decreases the salience of social defeat). Males, which might have lower oxytocin signaling during defeat, would then be protected from the effects of social defeat by supplementation with exogenous oxytocin as we found here. Basal sex differences in oxytocin acting in the VTA could also explain why oxytocin treatment did not decrease the salience of social defeat in females (i.e., basal oxytocin signaling is already high during social defeat), and why oxytocin antagonism did not increase the salience of social defeat in males (i.e., basal oxytocin signaling is already minimal during social defeat). This intriguing possibility warrants further investigation. This could, perhaps, also be related to sex differences in “dose response curves” to positive and negative valence social stimuli [12, 25, 27, 28]. It is, of course, also possible that the effects of manipulating oxytocin signaling in females could vary over the estrous cycle, and this possibility could be explored in future studies.

These data also suggest that oxytocin signaling in the VTA does not enhance the salience to negatively-valenced social stimuli, which is contrary to the social salience hypothesis [8]. However, there is growing evidence that oxytocin might function in other nodes of the social decision making network to modify responses to negatively valenced stimuli [7, 35]. For example, social vigilance appears to be modified by oxytocin neurons and receptors in the bed nucleus of the stria terminalis (BNST) [36, 37]. Therefore, oxytocin acting in other areas that express oxytocin receptors [33, 41] and that are known to modify responses to social stress, such as the BNST, medial prefrontal cortex, or amygdala [38–40] might underlie oxytocin’s ability to increase the salience of negatively-valence social stimuli. This intriguing possibility requires further examination.

Interestingly, there was no effect of drug treatment on social vigilance (Fig. 2) or social investigation (Fig. 3). Not surprisingly, though, social defeat was associated with more social avoidance (Fig. 1) and social vigilance (Fig. 2), along with less social investigation (Fig. 3), which is consistent with previous research [27]. Taken together, these data suggest that oxytocin’s effects, at least withing the VTA, are specific to social avoidance and do not significantly alter other aspects of defeat-induced social anxiety. It is possible that manipulating oxytocin signaling in the BNST, medial prefrontal cortex, or amygdala, as discussed above, could significantly alter social vigilance or investigation as well as social avoidance. These possibilities should be examined in future studies.

Finally, it is important to note that the effect of oxytocin on social avoidance was not due to oxytocin specifically affecting social avoidance, given that drug was administered during the defeat training and not during the avoidance testing 24 hours later. Furthermore, no defensive behaviors from our subjects, nor aggressive behaviors expressed by the RAs, were altered by drug being on board during the defeat. Therefore, these data suggest that oxytocin in the VTA decreases the salience, or potential learning, of the social defeat experience.

In conclusion, oxytocin signaling in the VTA regulates the salience of social defeat in a similar manner between the sexes. Specifically, oxytocin antagonists are able to increase female social avoidance to male levels, while oxytocin treatment was able to decrease male social avoidance to female levels. This suggests that observed sex differences between females and males in their susceptibility to social stress may be mediated, in part, by sex differences in oxytocin signaling in the VTA, although future studies are needed to test this hypothesis. Finally, these results suggest that sex differences in the efficacy of oxytocin to alter negatively-valenced social interactions could have an immense impact on guiding the development of sex-specific pharmacotherapies to reduce the effects of social stress, emphasizing OTR agonism in males.

Highlights.

  • OT receptor antagonism in the VTA during defeat training increases later social avoidance in females

  • OT infused in the VTA during defeat training decreases later social avoidance in males

  • Overall, OT signaling in the VTA during defeat training reduces the later salience of social defeat

Funding:

This work was supported by the National Institutes of Health [Grant Numbers: R01MH110212, R01MH122622]

Footnotes

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