Perinatal fentanyl exposure drives enduring addiction risk and central amygdala gene dysregulation.

The use of fentanyl and other opioids during pregnancy is a pressing public health issue due to its association with Neonatal Opioid Withdrawal Syndrome (NOWS) and long-term neurobehavioral deficits. Human epidemiologic studies are confounded by both genetic and environmental factors that differ between exposed and unexposed children. We developed a novel rat model of perinatal fentanyl exposure in heterogeneous stock (HS) rats characterized by high genetic diversity, to investigate NOWS symptoms and its long-term effects on adult fentanyl self-administration, drug-seeking behavior, and central amygdala (CeA) transcriptomic changes, addressing a critical gap in understanding synthetic opioid impacts. Offspring born to fentanyl-exposed dams exhibited reduced survival, lower body weight, spontaneous withdrawal symptoms, and mechanical hypersensitivity during adolescence. These rats displayed negative affect in adolescence, while they showed increased fentanyl self-administration, heightened drug-seeking during reinstatement, and elevated corticosterone levels during withdrawal in adulthood. To explore the molecular underpinnings of these physiological and behavioral outcomes, we conducted RNA-seq in the CeA of adult rats, revealing dysregulated pathways related to GPCR signaling, adaptive immune response and neurodevelopmental processes. These transcriptional changes provide insights into the mechanisms driving addiction vulnerability and stress-related behaviors following early fentanyl exposure. Our findings highlight the lasting impact of perinatal opioid exposure in an experimental system that avoids many of the confounds that plague studies in humans, underscoring the need for preclinical models to study NOWS and its long-term consequences. This model offers translational relevance for developing therapeutic strategies to mitigate NOWS and reduce neuropsychiatric risks associated with perinatal opioid exposure.