Abstract
Chronic stress can increase the risk of developing a substance use disorder in vulnerable individuals. Numerous models have been developed to probe the underlying neurobiological mechanisms, however, most prior work has been restricted to male rodents, conducted only in rats, or introduces physical injury that can complicate opioid studies. Here we sought to establish how chronic psychosocial stress influences fentanyl consumption in male and female C57BL/6 mice. We used chronic social defeat stress (CSDS), or the modified vicarious chronic witness defeat stress (CWDS), and used social interaction to stratify mice as stress-susceptible or resilient. We then subjected mice to a 15 days fentanyl drinking paradigm in the home cage that consisted of alternating forced and choice periods with increasing fentanyl concentrations. Male mice susceptible to either CWDS or CSDS consumed more fentanyl relative to unstressed mice. CWDS-susceptible female mice did not differ from unstressed mice during the forced periods, but showed increased preference for fentanyl over time. We also found decreased expression of nucleus accumbens Rho GTPases in male, but not female mice following stress and fentanyl drinking. We also compare fentanyl drinking behavior in mice that had free access to plain water throughout. Our results indicate that stress-sensitized fentanyl consumption is dependent on both sex and behavioral outcomes to stress.
Highlights
Repeated and severe stress has long been associated with the emergence of psychiatric disorders including substance use disorders (Sinha, 2008; Hollon et al, 2015; Sapolsky, 2015; Newman et al, 2018; Wemm and Sinha, 2019)
As concentration increased in forced epoch 2 and 3, chronic witness defeat stress (CWDS) males consumed more fentanyl relative to unstressed males
We found a sex difference that reached significance at forced epoch 3, with unstressed female mice consuming more fentanyl than unstressed males
Summary
Repeated and severe stress has long been associated with the emergence of psychiatric disorders including substance use disorders (Sinha, 2008; Hollon et al, 2015; Sapolsky, 2015; Newman et al, 2018; Wemm and Sinha, 2019). The effects of psychosocial stress on substance use are often divergent and depend on the drug, stress duration, and species [reviewed in Neisewander et al (2012)]. In mice, prolonged social stress either promotes or suppresses cocaine self-administration (Yap and Miczek, 2007; Han et al, 2015, 2017; Arena et al, 2019) but we recently showed this depends on individual stress-response and social housing conditions (Engeln et al, 2021). There are comparatively fewer studies on psychosocial stress and opioid self-administration. Social stress does not influence heroin self-administration (Cruz et al, 2011), while in mice it is associated with increased morphine preference (Cooper et al, 2017)
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