Intra‐uterine Exposure to Diazepam Decrease the Ventilatory Response and Impairs the Motor Behavior of Males and Females at Post‐natal Life

Abstract

Gestation is a critical period for the development of the respiratory system and interventions, such as the use of benzodiazepines (BZs) for treatment of psychic disorders, at this stage, may compromise this system. BZs, such as Diazepam (DZ) are one of the most common drugs prescribed to treat anxiety disorders but it can compromise the development of the respiratory system during the gestational period since it crosses the placental barrier binding at GABAA receptors. Despite of your widely prescription, it is still unknown the real consequences of the administration DZ during pregnancy on breathing control during post‐natal life. We administered DZ (1mg/Kg) or its vehicle, via osmotic pump, to pregnant rats during whole pregnancy (21 day) to understand the consequences of intra‐uterine exposure to DZ on the ventilatory responses of newborns rats. We used newborns rats (male and female) at post‐natal (P) day 0 (P0), P12 and P21. After 4 hours of their birth we evaluated chewing reflex and straightening reflex. Ventilation (Ve), tidal volume (VT), respiratory frequency (fR) and oxygen consumption (VO2) were measured by using head‐out plethysmograph for P0 and P12 and using whole‐body plethysmograph for P21. Animals were exposed to normocapnic‐normoxic, hypercapnia (7% CO2) and hypoxia (10% O2). The project was approved by the local ethics committee: CEUA Protocol: 2164/17. DZ treatment of the dams decreased gestational length compared to control group but did not affect the number of male and female pups as well did not affect the total number of pups per litter. There are no differences on the average of number of chewing or on straightening reflex time although we have observed that the treated animals show less variability on chewing reflex compared with their same gander control group. At P21, both treated males and females have shown a higher body weight compared to their control group. Under room air conditions, P0 treated females shown a decrease in their fR and VO2, P12 treated males shown a reduction in their Ve due a reduction in their VT and P21 treated males have a decrease on Ve and it was due a reduction on their VT and they also have a reduction on their Ve/VO2. Under hypercapnia, P0 treated males have decrease in their fR, P0 treated females have a decrease in their Ve due a reduction in their VT, P12 treated males have a decrease on fR and VO2, P12 treated females have a decrease in their Ve due a reduction in their VT and a reduction in their Ve/VO2. Under hypoxia, P0 treated females show a decrease on VT, P12 treated animals have a decrease in their Ve. Intra‐uterine exposure to diazepam reduces male ventilation at baseline, which may lead the need to use vital support for maintain their correct oxygenation. Regard reduction on treated females’ ventilation under hypercapnic but not at baseline or hypoxia, we suggest that central chemosensitivity of this group is decreased.Support or Funding InformationFinancial Support: FAPESP (2017/26367‐9) and CNPq.