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Prenatal opioid exposure inhibits microglial sculpting of the dopamine system selectively in adolescent male offspring


The current opioid epidemic has dramatically increased the number of children who are prenatally exposed to opioids, including oxycodone. A number of social and cognitive abnormalities have been documented in these children as they reach young adulthood. However, little is known about the mechanisms underlying developmental effects of prenatal opioid exposure. Microglia, the resident immune cells of the brain, respond to acute opioid exposure in adulthood. Moreover, microglia are known to sculpt neural circuits during typical development. Indeed, we recently found that microglial phagocytosis of dopamine D1 receptors (D1R) in the nucleus accumbens (NAc) is required for the natural developmental decline in NAc-D1R that occurs between adolescence and adulthood in rats. This microglial pruning occurs only in males, and is required for the normal developmental trajectory of social play behavior. However, virtually nothing is known as to whether this developmental program is altered by prenatal exposure to opioids. Here, we show in rats that maternal oxycodone self-administration during pregnancy leads to reduced adolescent microglial phagocytosis of D1R and subsequently higher D1R density within the NAc in adult male, but not female, offspring. Finally, we show prenatal and adult behavioral deficits in opioid-exposed offspring, including impaired extinction of oxycodone-conditioned place preference in males. This work demonstrates for the first time that microglia play a key role in translating prenatal opioid exposure to changes in neural systems and behavior.

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Fig. 1: Prenatal opioid exposure impacts neonatal outcomes in offspring.
Fig. 2: Prenatal oxycodone exposure increases D1R density in the NAc in adulthood in males but not females.
Fig. 3: Prenatal opioid exposure decreases microglial engulfment of NAc-D1R during adolescence in males.
Fig. 4: Prenatal opioid exposure prevents extinction of oxycodone-conditioned place preference in adult male, but not female, offspring.


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We thank all the members of the Bilbo lab for their critical reading of the manuscript, as well as Dr. Ravikiran Raju for providing his clinical insight as a neonatologist. We thank the Animal Care staff at McLean Hospital for providing excellent animal care and the staff of the Duke Light Microscopy Core for assistance with learning and trouble-shooting confocal microscopy.


This work was supported by NIH R21DA048399 to EHC and SDB, NIH F32ES029912 to CJS, and by a Harvard University Mind, Brain, and Behavior Faculty Research Award to EHC and SDB.

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EHC, SDB, CJS, and TL designed the study. CJS, TL, MJC, KEM, NC, AA, YAC, VJK, and YCJ conducted experiments. CJS, EHC, and SDB wrote the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Caroline J. Smith.

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Smith, C.J., Lintz, T., Clark, M.J. et al. Prenatal opioid exposure inhibits microglial sculpting of the dopamine system selectively in adolescent male offspring. Neuropsychopharmacol. 47, 1755–1763 (2022).

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