Investigating the neuroinflammatory regulation of social stress‐induced anxiety and opioid seeking between the sexes

Abstract

Exposure to social stress leads to psychiatric conditions such as substance abuse, anxiety, and post‐traumatic stress disorder in susceptible individuals. Importantly, these conditions disproportionately affect females as compared to males, yet studies conducted in females are lacking. Further, neuroinflammation has been identified as a possible mechanism underlying this susceptibility and may link stress exposure to increased drug intake, especially for opioids. Thus, these experiments seek to further identify if ethologically relevant models of social stress that increase anxiety‐like behavior in male and female rodents also increase susceptibility to substance abuse. Our lab has characterized the witness stress paradigm in rats, where a female observes the sensory aspect of social defeat stress between two males. Previous work indicates that females are especially sensitive to the physiological and behavioral effects of this stressor due to lasting increases in neuroinflammation. The current study was completed to determine if we can predict susceptibility to social stress induced neuropsychiatric disorders by measuring behavioral responses to predator odor and if we can identify distinct physiological and neuronal markers related to stress susceptibility that are linked to increased drug seeking behavior. Specifically, adult male and female rats were first exposed to ferret odor and freezing behaviors were quantified to separate animals into high and low freezing clusters using a K‐means cluster analysis. Males were then exposed to 5 daily social defeat episodes while females observed from within the cage. To measure anxiety‐like responses to fear related cues, all rats were subsequently exposed to the ferret odor context and, 24‐hours later, the social stress context to determine the behavioral and physiological effects of these cues. These experiments found that exposure to the predator odor delineates two separate phenotypes – high and low freezing groups – for both male and female rats. Further, this behavioral phenotype predicts the level of anxiety‐like behavior that is exhibited in response to the presentation of fear‐related cues. Blood samples collected following the initial predator odor exposure and after fear cue presentation are being analyzed to determine corticosterone levels while brain tissue collected after fear cue exposure will allow us to identify the extent of the neuroinflammatory response. Current experiments using opioid conditioned place preference testing in stressed animals along with the administration of an anti‐inflammatory agent are being completed to identify the role of this stress‐induced neuroinflammation in opioid abuse. These results will ultimately allow us to elucidate the behavioral, physiological, and neuronal impact of stress exposure that contributes to increased substance abuse and will identify novel anti‐inflammatory therapeutics that can be used for the clinical prevention and treatment of these disorders.