Adolescent morphine exposure impairs cognitive flexibility in female but not male mice.

Use of prescription opioids continues to rise, especially in adolescent individuals. As adolescence is a critical development window for higher order cognitive functions, thus opioid exposure during this period may have significant long-lasting effects on cognitive function and predisposition individuals to be at greater risk of developing opioid use later in life. Here, we examine previously explored effects of opioid exposure during adolescence on affect-related behavior, motivation, and cognitive flexibility. We find that a two-week exposure to non-contingent morphine during adolescence (i.e., post-weaning) does not alter performance in an elevated plus maze, forced swim test, or motivation for appetitive reward in male or female mice when tested during adolescence or adulthood. Examination of how adolescent morphine impacts cognition revealed impairments in visual-based discriminative learning and cognitive flexibility in female but not male mice, as assessed using an operant-based attentional set-shifting task. Unexpectedly, deficits in discriminative learning are observed when testing occurred during adolescence but not adulthood, whereas impaired performance in the extradimensional shift remained impaired into adulthood. The data indicate that opioid exposure during adolescence has a greater impact on cognitive function in female mice and that these deficits may be more widespread during acute withdrawal periods, while deficits in flexibility more enduring.