Rationale: Stress exposure has a lasting impact on motivated behavior and can exacerbate existing vulnerabilities for developing a substance use disorder. Several models have been developed to examine how stressful experiences shape drug reward. These range from locomotor sensitization and conditioned place preference to the propensity for drug self-administration or responding to drug-predictive cues. While self-administration studies are considered to have more translational relevance, most of the studies to date have been conducted in rats. Further, many self-administration studies are conducted in single-housed animals, adding the additional stressor of social isolation. Objectives: We sought to establish how chronic social defeat stress (CSDS) and social housing conditions impact cocaine self-administration and cocaine-seeking behaviors in C57BL/6 mice. Methods: We assessed self-administration behavior (cocaine or saline, 0.5 mg/kg/infusion) in C57BL/6 mice subjected to 10-day CSDS or in unstressed controls. Mice were housed either in pairs or in isolation during self-administration. We compared the effect of housing on acquisition of self-administration, seeking, extinction, drug-induced reinstatement, and after re-exposure to the social stressor. Results: Pair-housing during self-administration revealed increased social avoidance after CSDS is associated with decreased cocaine intake. In contrast, single-housing revealed stress-sensitive cocaine intake, with increased social avoidance after CSDS associated with increased early cocaine intake. Pair-, but not single-housed mice are susceptible to drug-induced reinstatement independent of CSDS history. Stress re-exposure sensitized cocaine-seeking in stressed single-housed mice. Conclusions: The social context surrounding cocaine intake can bidirectionally influence cocaine-related behaviors after psychosocial stress and should be considered when studying stress and drug cross-sensitization.
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