229 - Treatment with Erythropoietin and Melatonin Repairs Deficits of Attention Following Prenatal Opioid Exposure

Poster Number: 229
Publication Number: 229.143

O. Angel Odukoya, Johns Hopkins University School of Medicine, Bowie, MD, United States; Nethra Madurai, Johns Hopkins Hospital, Lutherville-Timonium, MD, United States; Yuma Kitase, Johns Hopkins school of Medicine, Baltimore, MD, United States; Shenandoah Robinson, Johns Hopkins Children's Center, Baltimore, MD, United States; Lauren Jantzie, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Background: Perinatal opioid exposure (POE) has deleterious effects on the developing brain. An urgent need exists to define the full spectrum of adverse outcomes associated with POE, elucidate key mechanisms, and identify therapies. Attention Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder. POE is significantly associated with the highest childhood risk of ADHD when compared to other commonly abused substances. We hypothesized that POE induces deficits of attention that persist into adulthood and are amenable to neurorepair by neonatal erythropoietin (EPO) and melatonin (MLT) administration.

Objective:
To examine the effect of POE on attention using a touchscreen platform and evaluate the effects of therapy directed neurorestoration with EPO and MLT.


Design/Methods: Osmotic mini pumps were implanted in pregnant Sprague Dawley rat dams for 28 days of continuous methadone (12mg/kg, 0.25μL/h) or saline infusion. A cohort of methadone-exposed pups was randomly allocated to receive EPO from postnatal day 1 (P1)-P5 at 2500U/kg/dose and MLT from P1-P10 at 20mg/kg. Commencing at P60, attention was assessed on a touchscreen platform using a 5-choice serial reaction time test (5CSRTT). Differences were compared using a two-way ANOVA with Bonferroni post-hoc correction with p < 0.05 as significant (n = 16-22/group).

Results: Animals with POE committed more errors (POE: 168.2±20.1, saline: 51.5±12.4, p = 0.0008) and had more omissions compared to animals receiving saline (POE: 2.6±0.7, saline: 0.7±0.2, p = 0.0063). Notably, EPO+MLT improved attention by reducing error rate and omission rate (POE + EPO/MLT: 55.375± 0.5 errors, 0.4±0.2 omissions; p < 0.01 for both). Of note, animals with POE exhibit deficits in attentional control seen by more premature responses (p < 0.01).

Conclusion(s): Adult animals with POE have profound deficits of attention similar to children exposed to opioids. POE is responsive to a mechanistically targeted therapy of EPO+MLT indicating novel therapeutic options for countless children with POE born each year. Biobehavioral biomarkers may be useful to identify patients with POE in need of treatment and assess therapeutic response. Further investigation into mechanisms of injury and repair, and effect of treatment efficacy on timing of treatment are necessary to improve long-term outcomes of children born from perinatal opioid exposure.