Perinatal Fentanyl Exposure Leads to Lasting Behavioral Vulnerabilities and Altered in the Central Amygdala in Rats
Opioid use during pregnancy is a growing public health concern, with in utero exposure to synthetic opioids like fentanyl linked to Neonatal Opioid Withdrawal Syndrome (NOWS) and long-term neurobehavioral impairments. However, the long-term neurodevelopmental consequences of in utero opioid exposure remain poorly understood. We developed a translationally relevant rat model of perinatal fentanyl exposure to investigate the behavioral and molecular outcomes of prenatal opioid exposure. Offspring born to fentanyl-exposed dams showed reduced survival rates, lower body weight, and spontaneous withdrawal symptoms. In adolescence, they displayed mechanical hypersensitivity and behaviors consistent with negative affect. In adulthood, these rats exhibited enhanced fentanyl self-administration, increased reinstatement behavior, and elevated plasma corticosterone levels during withdrawal. Furthermore, they showed increased risk-taking behavior in the Elevated Plus Maze, suggesting altered anxiety or impulsivity regulation. To investigate molecular correlates of these phenotypes, we performed transcriptomic profiling of the central amygdala of adult rats. Differential gene expression and gene set enrichment analyses revealed that perinatal fentanyl exposure led to dysregulation of pathways involved in synaptic signaling, neurodevelopment, GPCR signaling, and immune responses. These transcriptional changes provide a molecular framework for understanding how early fentanyl exposure leads to long-lasting vulnerability to stress and addiction-related behaviors. These findings underscore the lasting impact of perinatal opioid exposure on brain function and behavior and support the utility of this model for translational research on NOWS and opioid-related neuropsychiatric risk. Overall design: RNA-seq from the Central Amygdala of Rats was performed after perinatal exposure to fentanyl or saline. Brain tissues were collected in adulthood, 1 day after the last IVSA session. Each condition included 8 offspring (6 males and 2 females) from the perinatal treatment groups.