Prenatal diazepam exposure alters respiratory control system and GABAA and adenosine receptor gene expression in newborn rats.
In experimental animals, prenatal diazepam exposure has clearly been associated with behavioral disturbances. Its impact on newborn breathing has not been documented despite potential deleterious consequences for later brain development. We addressed this issue in neonatal rats (0-2 d) born from dams, which consumed 2 mg/kg/d diazepam via drinking fluid throughout gestation. In vivo, prenatal diazepam exposure significantly altered the normoxic-breathing pattern, lowering breathing frequency (105 vs. 125 breaths/min) and increasing tidal volume (16.2 vs. 12.7 mL/kg), and the ventilatory response to hypoxia, inducing an immediate and marked decrease in tidal volume (-30%) absent in controls. In vitro, prenatal diazepam exposure significantly increased the respiratory-like frequency produced by pontomedullary and medullary preparations (+38% and +19%, respectively) and altered the respiratory-like response to application of nonoxygenated superfusate. Both in vivo and in vitro, the recovery from oxygen deprivation challenges was delayed by prenatal diazepam exposure. Finally, real-time PCR showed that prenatal diazepam exposure affected mRNA levels of alpha1 and alpha2 GABAA receptor subunits and of A1 and A2A adenosine receptors in the brainstem. These mRNA changes, which are region-specific, suggest that prenatal diazepam exposure interferes with developmental events whose impact on the respiratory system maturation deserves further studies.
Picard
Nathalie
N
DMAG, Université de Picardie Jules Verne, Amiens 80036, France.
Guénin
Stéphanie
S
Perrin
Yolande
Y
Hilaire
Gérard
G
Larnicol
Nicole
N
D000818:Animals; D000831:Animals, Newborn; D003975:Diazepam / Q000633:toxicity*; D005260:Female; D018757:GABA Modulators / Q000633:toxicity*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D000860:Hypoxia / Q000235:genetics / Q000503:physiopathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000187:drug effects; D043705:Receptor, Adenosine A2A / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000235:genetics; D018047:Receptors, Purinergic P1 / Q000187:drug effects* / Q000235:genetics; D012119:Respiration / Q000187:drug effects*; D012125:Respiratory Center / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D015656:Respiratory Mechanics / Q000187:drug effects; D013990:Tidal Volume / Q000187:drug effects
D018757:GABA Modulators; C546242:Gabra1 protein, rat; C520011:Gabra2 protein, rat; D012333:RNA, Messenger; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D011963:Receptors, GABA-A; D018047:Receptors, Purinergic P1; D003975:Diazepam