Prenatal methadone exposure impairs adolescent cognition and GABAergic neurodevelopment in a novel rat model of maternal methadone treatment

Abstract

Methadone maintenance treatment (MMT) is the most common treatment for opioid-dependent pregnant women worldwide. Despite its widespread use, MMT is associated with a variety of adverse neurodevelopmental outcomes in exposed offspring, particularly cognitive impairments. The neurobiological abnormalities underlying these cognitive impairments are, however, poorly understood. This is, in part, due to a lack of animal models that represents the standard of care that methadone is administered in the clinic, with inconsistencies in the timing, doses and durations of treatment. Here we describe the characterisation of a clinically relevant rat model of MMT in which the long-term behavioural and neurobiological effects of prenatal methadone exposure can be assessed in adolescent offspring. Female Sprague-Dawley rats were treated orally with an ascending methadone dosage schedule (5, 10, 15, 20, 25 and 30 mg/kg/day), self-administered in drinking water prior to conception, throughout gestation and lactation. Pregnancy success, maternal gestational weight gain, litter survival and size were not significantly altered in methadone-exposed animals. Methadone-exposed offspring body and brain weights were significantly lower at birth. Novel object recognition tests performed at adolescence revealed methadone-exposed offspring had impaired recognition memory. Furthermore, the rewarded T-maze alternation task demonstrated that methadone-exposed female, but not male, offspring also exhibit working memory and learning deficits. Immunoblots of the adolescent prefrontal cortex and hippocampus showed methadone-exposed offspring displayed reduced levels of mature BDNF, in addition to the GABAergic proteins, GAD67 and parvalbumin, in a sex- and brain region-specific fashion. This rat model closely emulates the clinical scenario in which methadone is administered to opioid-dependent pregnant woman and provides evidence MMT can cause cognitive impairments in adolescent offspring that may be underlined by perturbed neurodevelopment of the GABAergic system.