Adolescent prefrontal and amygdala molecular signatures of perinatal morphine versus buprenorphine exposure in mice.

Buprenorphine (BUP) treatment during pregnancy reduces overdose risk and attenuates adverse neonatal outcomes compared to full μ-opioid receptor agonists. Yet, prenatal exposure to BUP and other opioids is associated with long-term executive function deficits in children. Prenatal BUP exposure also relates to reductions in neonatal amygdala volume. To assess the impact in offspring brain regions relevant to these clinical findings and in the absence of clinical confounds, we examined the effects of perinatal BUP versus morphine (MO) on the offspring prefrontal cortex (PFC) and basolateral amygdala (BLA) in adolescent mice. Female mice were given once daily s.c. injections of low dose BUP (0.1 mg/kg, n = 8), MO (10 mg/kg, n = 12), or saline (SAL, n = 10) during pre-gestation, gestation, and lactation until offspring were weaned. We conducted RNA sequencing and immunohistochemistry in the PFC and BLA at postnatal day (P)39. Offspring exploratory and social behavior were assessed, as well as puzzle box performance in early adulthood. MO increased expression of microglia markers in male offspring at the transcriptional (Csf1r, Cx3cr1, P2ry12) and protein (CD68, IBA1) level that was prominent in the PFC, while CD68 increases were also evident in the BLA with BUP. Female BUP offspring had the greatest numbers of differentially expressed genes, especially in the BLA. Expression patterns related to downregulation of genes involved in neuron growth and upregulation of immediate early genes. MO subtly impaired puzzle box performance in females, while MO and BUP decreased thigmotaxis behavior in the open field in males. Overall, perinatal MO exposure affects microglia markers, particularly in adolescent male offspring. The BLA may be particularly sensitive to the effects of perinatal BUP exposure despite subtle behavioral changes.