Long term impact of maternal opioid use and management strategies on neurodevelopment in rodent offspring

About This Grant

Project Summary The overall goal of this project is to evaluate the long-term impact of in utero oxycodone exposure, opioid maintenance therapy and opioid-withdrawal mitigation strategies on neuro-behavioral development, brain structure and volume and reward processing. Clinical studies have shown concerning long-term, neurodevelopmental outcomes associated with in utero opioid exposure, which include lower social competence scores, memory deficits, and increased risk for behavioral problems and hyperactivity disorders. Clinical data is limited due to a number of challenges, including quality of maternal-infant bonding and care, maternal poly- substance use, epigenetic influences, and socio-economic factors. Given these limitations there is a unique opportunity for mammalian experimental models to investigate the long term effects of in utero opioid exposure, maintenance replacement therapy, as well as opioid withdrawal mitigation treatments on neurobehavioral outcomes. In the first aim we will evaluate the impact of opioid maintenance therapies (methadone and buprenorphine) on offspring, following in utero exposure to oxycodone in dams extending from conception to parturition or through pup weaning. We will also characterize the long-term behavioral impact of clinically- approved opioid withdrawal mitigation treatments, methadone and morphine, as well as buprenorphine in pups, following in utero exposure to oxycodone. In the second aim we will look to correlate changes in brain structure and volume using magnetic resonance imaging in pups following the opioid maintenance therapy in the dams as well as opioid withdrawal mitigation strategies in the pups. In the final aim we will examine whether prenatal opioid exposure and opioid maintenance or withdrawal mitigation strategies disrupt reward processing at the circuit level by examining GABAergic projections from the ventral tegmental area to the nucleus accumbens shell that we have previously shown to modulate reward behavior. Together, this approach will allow us to determine the long-term neuro-behavioral and anatomical changes that occur following in utero oxycodone-exposed pups following: 1) Opioid maintenance therapies in dams and 2) opioid withdrawal mitigation treatments in pups. We hypothesize, that this will impair learning, alter social and reward behavior, induce anxiety- and depressive- related behaviors, and reduce sensitivity to tactile and pain sensation (aim 1); decrease volume in a number of brain regions involved in reward processing and cognitive function such as the basal ganglia, thalamus, hippocampus and amygdala, change amygdalar functional connectivity as well as cause microstructural damage in the corpus callosum (aim 2); increase rewarding valance of GABAergic projection from the ventral tegmental area to the nucleus accumbens shell (aim 3). We hypothesize that exposure to buprenorphine may improve these outcomes due it’s activity at the kappa opioid receptor system. Understanding the long-term impact of oxycodone exposure in tandem with opioid maintenance therapy and opioid withdrawal mitigation strategies will allow us to explore treatment strategies and/or targets that may limit these long-term negative consequences.