Relapse to opioids facilitated by witnessing the distress of another is mediated by the activity of oxytocin: a preclinical model of the neural substrates of the relationship between secondary trauma and addiction

Abstract

Abstract Opioid abuse poses a grave danger to human life and has been declared a Public Health Emergency in the US. In 2018 alone, prescription opioids were the most commonly reported substance exposure to poison control centers, with cases soaring to near 300 000. 44% of cases were of children under the age of 5, with over 5000 exposures to heroin and fentanyl. These trends increased since 2018 and accounted for a reduced life expectancy in the US. Indeed, in the US alone, 2.5 million adults are afflicted by opioid addiction, which claims close to 50,000 deaths per year. Efforts to quit are frequently short-lived at best, while the incidence of relapse over the longer term is considerable. Psychosocial stress and addiction liabilitySevere stress plays a powerful role in the vulnerability to both addiction and relapse, perhaps contributing to the marked rates of relapse (75%) to opioid addiction. Indeed, it is well established in both preclinical and human studies that stress confers vulnerability to drug use and the perpetuation of abusing drugs, as well as relapse to addiction. Despite the abundance of data exposing stress as a critical factor in drug seeking and relapse to drug taking, the underlying neural circuitry implicated in the relationship between stress and relapse to drugs remains poorly understood. Animal models of addiction are useful tools in attempting to elucidate mechanisms responsible for drug-seeking habits. Animal models are also widely used to examine the biological and physiological underpinnings of behavior in health and disease as it pertains to humans. Critically, however, much of this research fails to capture a key stressor in humans: witnessing the trauma of another, especially of a familiar or close person. The significance of such forms of stress in humans is evident by the increased vulnerability to and prevalence of PTSD and drug addiction among those who have witnessed the suffering or death of others. Here, we propose a novel paradigm to attempt to model social stressors as contributing to reinstatement of drug seeking in mice . A Novel paradigm for the study of Observational Distress and reinstatement of opioid-seekingI propose that the susceptibility to PTSD, addiction, and addiction relapse conferred through observing another’s distress is mediated by the assumption in the witness of an affective state that closely matches that of the one in distress. This tendency to match the emotional state of another, also called “Affective State Matching” (ASM) is central to human empathy. Although vicarious emotional experiences underlie prosocial behaviors and the development of compassion in humans (as well as prosocial and consolation behaviors in other mammals), they also enable the development of stress-induced disorders if the witnessed distress is sufficiently potent. Previous work in our lab has focused on understanding the neural underpinnings of vicarious fear using mouse dyads. We have demonstrated that fear-associated ASM can be elicited in experimental settings and shown that this phenomenon is dependent on the activity of oxytocin- a neuropeptide involved in sociality, empathy, and affiliation. Since vicarious distress is known to precipitate relapse to drug addiction, is a common precursor to PTSD in humans, and drug addiction and PTSD are often comorbid, it is possible that oxytocin facilitates relapse to drug addiction following vicarious distress. Does observational distress facilitate reinstatement of morphine-conditioned place preference? Effects of familiarity and sex.To establish whether witnessing another’s distress can reliable predict reinstatement to opioid seeking, I expose male and female mice to a biased design morphine-conditioned place preference CPP) task to first elicit the preference for morphine. Mice readily acquire a preference for the morphine-paired context relative to a compartment associated with the administration of a vehicle. Once CPP is established, mice undergo an extinction phase, the aim of which is to reverse the acquired morphine preference. This allows the testing of reinstatement of morphine seeking following observational distress. Again, male and female mice successfully extinguished mCPP. Same-sex mice were then randomly assigned to one of two roles: Observer or Demonstrator. The Demonstrator was placed in a compartment adjacent to a natural predator, a large male rat, who had been administered cocaine (20mg.kg) to enhance locomotive activity. The Observer lacked visual access to the rat and was only exposed to the behaviors exhibited by the Demonstrator during this task. Since previous studies in our lab have revealed that mice show a familiarity bias which may affect behavior in response to the distressed Demonstrator, we included both familiar (cage mates) and unfamiliar (non-cage mates) Observer-Demonstrator dyads. Demonstrators and Observers exhibited distinct, coordinated threat-associated behaviors, with Demonstrators showing increased territorial defensive aggression, attempts to escape, and threat assessment, while the Observer attempted approaching the distressed conspecific.We found that exposure to predator threat was sufficient to produce reinstatement of CPP in Demonstrators. Male Observers, however, reinstated CPP only if they were familiar with the distressed Demonstrator. Such a familiarity bias was lacking in female mice. Does Demonstrator distress predict magnitude of Observer reinstatement of CPP? Effects of familiarity and sex.We found that behavioral manifestations of ethologically relevant threat responses in Demonstrators predicted the magnitude of reinstatement of CPP in familiar but not unfamiliar Observers. Female Observers reinstated CPP regardless of their familiarity with the Demonstrator-a finding consistent with our previous reports. Does Oxytocin modulate observational distress and subsequent reinstatement? To examine the aforementioned hypothesis that oxytocin is implicated in the social transmission of distress, we administered either intranasal oxytocin, or an oxytocin antagonist, to observer animals. Since we expected oxytocin to reverse the effect of familiarity, we administered oxytocin to Unfamiliar Observers (male). Similarly, to establish whether familiar Observers’ distress behaviors were dependent on oxytocinergic activity, we administered the oxytocin antagonist in familiar Observers. Oxytocin administration reliably induced reinstatement in Unfamiliar male Observers, thus rescuing the familiarity bias, while oxytocin antagonism blocked reinstatement of CPP in familiar male Observers. These effects of oxytocin activity on Observational Distress were reflected in reduced stress-related behaviors in the familiar Observer cohort. Control experiments are described. Since female Observers reinstated the previously extinguished preference for morphine regardless of familiarity with the conspecific, we investigated whether administration of an oxytocin antagonist would rescue this effect. Indeed, both familiar and unfamiliar female Observers failed to reinstate morphine-CPP, lending further support to the hypothesis that oxytocin is implicated in mounting a stress response to the distress of a fellow conspecific. Similarly, behavioral indexes of stress-responsivity were altered in both Observer cohorts. Once again, control manipulations are described. Does witnessing the distress of another impact social interactions between Observer and Demonstrator?Bearing witness of the plight of another is associated with an elevated risk of PTSD in humans. In turn, PTSD following such exposure is frequently comorbid with altered, often aggressive, social interactions, especially against familiar individuals, such as family members or friends. To examine whether Observational Distress in our task was sufficient to alter social interactions in participating animals, we assessed social interaction between Observers, Demonstrators, and mice who were not included in the experiment. We find that familiar, but not unfamiliar male Observers exhibited consistent aggression toward the Demonstrator, indicated by numerous attacks, bites, and chasing. Interestingly, Observers did not act aggressively toward the naïve conspecific in the home cage, indicating that aggression was related to the experience of observing distress in the Demonstrator and exhibiting defensive aggression as a result. Oxytocin antagonism eliminated social aggression in familiar Observer males, further confirming a role of oxytocin in the acquisition of and responding to social distress cues. Unlike male Observers, neither familiar nor unfamiliar female Observer mice acted aggressively following Observational Distress. Does social aggression following observational distress coincide with social rank in males?Cohabiting mice quickly form social hierarchies of dominance and subordination. Social dominance or subordination can affect the propensity of a mouse to act aggressively or flee to signal subordination and terminate attacks quickly. Thus, it is possible that mouse social aggression following Observational Distress coincided with dominant status in Familiar male Observers, and that the two are thereby confounded. To disambiguate social rank and aggression, we assessed social dominance status in a randomly selected group of males using a variant of the Tube Test. This task afforded the determination of rank in mice housed in groups of four relative to each member of the home cage. Mice were then assigned blindly to an Observer or Demonstrator role and subsequently assessed for social interaction. We found that Familiar Observers acted aggressively toward Demonstrators regardless of social rank and concluded that social aggression after witnessing a Demonstrator in distress was not confounded by social status. The implications, caveats, and findings of these experiments are discussed, and directions for future work are proposed.