Neurodevelopmental and behavioral consequences of perinatal exposure to the HIV drug efavirenz in a rodent model

• Published in: Translational psychiatry 2019-02, Vol.9 (1), p.84, Article 84
• Main Authors: van de Wijer, Lisa, Garcia, Lidiane P., Hanswijk, Sabrina I., Rando, Juliette, Middelman, Anthonieke, ter Heine, Rob, Mast, Quirijn de, Martens, Gerard J. M., van der Ven, André J. A. M., Kolk, Sharon M., Schellekens, Arnt F. A., Homberg, Judith R.
• Format: Article
• Language: English
• Subjects: 13/1; 14/34; 14/63; 631/378/340; 692/699; 82/1; 82/51; Animals; Antiretroviral drugs; Behavioral Sciences; Benzoxazines - pharmacology; Biological Psychology; Body Weight - drug effects; Developmental Disabilities - chemically induced; Female; HIV Infections - drug therapy; Male; Medicine; Medicine & Public Health; Motor Activity - drug effects; Motor Cortex - cytology; Motor Cortex - pathology; Neurons - cytology; Neurons - drug effects; Neurosciences; Pharmacotherapy; Pregnancy; Prenatal Exposure Delayed Effects - chemically induced; Psychiatry; Rats; Rats, Wistar; Reflex, Startle; Serotonin - metabolism
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/s41398-019-0420-y

Efavirenz is recommended as a preferred first-line drug for women of childbearing potential living with human immunodeficiency virus. Efavirenz is known for its central nervous system side effects, which are partly mediated by serotonergic actions. The neurotransmitter serotonin exerts neurotrophic effects during neurodevelopment and antenatal exposure to serotonergic agents has been linked to developmental delay. Although the teratogenic risks of efavirenz appear to be minimal, data on long-term developmental effects remain scarce. Here, we aimed to investigate the short- and long-term behavioral and neurodevelopmental effects of perinatal efavirenz exposure. We treated pregnant rats from gestation day 1 until postnatal day 7 with efavirenz (100 mg/kg) or vehicle. We measured behavioral outcomes in male offspring during the first 3 postnatal weeks, adolescence and adulthood, and conducted brain immunohistochemistry analyses after sacrifice. Perinatal efavirenz exposure resulted in reduced body weight and delayed reflex and motor development. During adulthood, we observed a decrease in the total number of cells and mature neurons in the motor cortex, as well as an increase in the number of Caspase-3-positive cells and serotonergic fibers. Together, our data show a developmental delay and persistent changes in the brain motor cortex of rats exposed to efavirenz perinatally. Because over 1 million children born annually are exposed to antiretroviral therapy, our findings underline the need for clinical studies on long-term neurodevelopmental outcomes of perinatal exposure to efavirenz.