Effects of prenatal methadone and buprenorphine exposure on motivated responding for sucrose and gene expression in adult male and female rats

• No effect of prenatal methadone or buprenorphine on weaning or adult weights • Prenatal methadone increased motivated responding for sucrose in males and females • Methadone-induced, female-specific increase in nucleus accumbens gene expression • Differential effects of methadone and buprenorphine in arcuate nucleus The opioid crisis has resulted in escalating rates of opioid use disorder in women of reproductive age and increased prevalence of fetal drug exposure. While medication for opioid use disorder (MOUD) – e.g., buprenorphine or methadone – improves maternal health outcomes, infants exposed to MOUD show a variety of physical and behavioral consequences. There are, however, few clinical or preclinical studies investigating long-term effects of MOUD exposure. The current work investigates the long-term effects of prenatal MOUD exposure on effort-based responding to a palatable food reward and gene expression in regions of the brain related to reward and feeding, including the nucleus accumbens and hypothalamus. Female Sprague Dawley rats were implanted with osmotic minipumps filled with methadone (10 mg/kg/day) or buprenorphine (1 mg/kg/day) or saline control (2.5 μL/hour for 28 days) and mated four days later. In adulthood, male and female offspring began sucrose pellet self-administration to assess the motivational strength of a food reward in MOUD-exposed animals compared to saline controls, followed by analysis of gene expression via RNAscope in situ hybridization. We observed long-term changes in reward motivation, where adults gestationally exposed to methadone – but not buprenorphine – demonstrated increased motivated responding for sucrose. We observed modest sex-dependent effects of MOUD on gene expression in the nucleus accumbens and arcuate nucleus of the hypothalamus following sucrose self-administration. These data suggest differential effects of methadone and buprenorphine on the brain and behavior, providing insight into the potential neuromolecular underpinnings of MOUD-induced changes in neural modulation of reward-motivated behavior.