Consequências da exposição intrauterina ao Diazepam: impacto sobre os sistemas ventilatório e monoaminérgico de ratos neonatos durante o desenvolvimento

Abstract

Anxiety is a problem that affects the general population, and women are twice as likely to develop such disorders, especially at reproductive age. Diazepam (DZP) is one of the drugs used to treat these disorders, but its use during pregnancy has been associated with problems for the fetus. This medication interacts with the GABAergic system, which participates in the respiratory control of mammals, as well as in the ventilatory responses to hypercapnia and hypoxia, acting in chemosensitive regions. Thus, we sought to evaluate the effects of intrauterine exposure to DZP (1 mg/Kg/day) on ventilation and metabolism, chewing and righting reflexes on the number of neurons in the catecholaminergic and serotonergic system of rats in different ages in the development (P0-1, P12-13, P21-22). Pressure and whole-body plethysmography and indirect calorimetry were used to assess ventilation and metabolism at P0-1, P12-13, P21-22. Free-floating immunofluorescence was used for the analysis of catecholaminergic and serotonergic neurons in P12-13. Chewing and righting reflexes were used to assess the behavior at P0-1. We observed that DZP-treated females showed increased respiratory frequency and metabolism in normoxia/normocapnia (P0-1), as well as decreased ventilation in hypercapnia (P0-1 and P12-13). Males treated with DZP showed a decrease in ventilation in normoxia/normocapnia (P12-13 and P21-22), a decrease in respiratory frequency in hypercapnia and a decrease in ventilation in hypoxia (P12-13). In P21-22, both males and females of DZP group showed body mass gain. Females and males treated with DZP in P12-13 have a lower number of catecholaminergic neurons, as well as males at this age have a reduction in the number of serotonergic neurons. These results show that DZP exposure during pregnancy promotes sex-specific long-lasting effects on ventilatory control and Central Nervous System and contributes to the understanding of drug interventions during the gestational period and the occurrence of adverse events for the newborn