Prenatal Venlafaxine Exposure-Induced Neurocytoarchitectural and Neuroapoptotic Degeneration in Striatum and Hippocampus of Developing Fetal Brain, Manifesting Long-term Neurocognitive Impairments in Rat Offspring

Abstract

Depression is a leading cause of disability which at its worst leads to suicide. Its treatment relies on psychotherapy in combination with certain antidepressants (AD_(s)) from various classes such as tricyclics, selective serotonin reuptake inhibitors, or serotonin and norepinephrine reuptake inhibitors (SNRIs). Among SNRIs, venlafaxine (VEN) is one such most commonly prescribed AD which is recently reported to be in the top 50 most prescribed drugs in the USA. Depression during pregnancy is a common condition, where prescribing an AD becomes necessary as untreated depression during pregnancy has its own complications for both mother and the child. This, probably, is why an incredible rise has been reported in prescribing ADs like VEN to pregnant women in the recent past, despite some studies, including the one from our own group, having reported the in-utero VEN-induced apoptotic neurodegeneration in the fetal neocortex and the consequent neurobehavioral anomalies in adulthood. However, there still exists a lack of insight into the effects of intrauterine exposures of VEN on other fetal brain regions like the hippocampus (HPC) and striatum (STR) and the consequent effects on their cognitive and emotional wellbeing in later life. Hence, this study has been conducted where pregnant Charles-Foster (CF) rats were oral gavaged with VEN (25, 40, and 50 mg/kg bw) from gestation day (GD) 05-19. On GD-19, half of the control and treated dams were euthanized to collect their fetuses. Fetal brains were dissected and processed for reactive oxygen species (ROS) estimation neurohistopathology and confocal microscopic studies. The remaining dams were allowed to deliver naturally, and litters were reared for up to 8 weeks then tested for their cognitive abilities by the Morris water maze test and for their emotionality by the Forced swimming test. Our results showed substantial neurocytoarchitectural deficits in both HPC and STR, along with enhanced ROS levels and apoptotic neurodegenerations. Furthermore, VEN-treated young rat offsprings displayed cognitive impairments and depressive behavior as the long-lasting impact of VEN in a dose-dependent manner. So it may be inferred that prenatal VEN-induced oxidative stress causes apoptotic neurodegeneration leading to neuronal loss in HPC and STR which consequently affects the development of the said brain areas resulting in impaired cognitive and emotional abilities of young adult offsprings. Therefore, extrapolating these findings in animal models, caution may be taken before prescribing VEN to pregnant women, especially during the sensitive phase of pregnancy.

Keywords: Antidepressants; Apoptosis; Fetal neurotoxicity; Hippocampus; Morris water maze; Neurocognitive Impairments; Neurodegeneration; Striatum; Venlafaxine.