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Evidence for Hormonal Imbalance after Methadone Treatment in Pregnant and Pseudopregnant Rats

Abstract The effects of methadone (METH) on the plasma estriol level and hormonal target tissues' cyclic nucleotides (cAMP and cGMP) were investigated in pregnant and pseudopregnant rats. In the pregnant animals, METH (5 mg/kg/day), given once daily from Days 6 to 15 of gestation, significantly reduced the maternal body weight gain in association with an increase in the number of dams bearing resorptions (56%) and a significant reduction in fetal body weight (33%). An inhibition of the plasma estriol level by METH was observed on Day 9 of gestation. Stimulation of the sympatho-adrenal axis and hypothalamo-pituitary axis by acute METH administration was observed and correlated with a significant increase in the levels of cyclic nucleotides in the uterus and adrenal glands of pregnant rats. However, tolerance to METH effects on cyclic nucleotide levels developed by Day 15 of gestation. METH also depressed the fetal cyclic nucleotide levels on Days 12 and 15 of gestation. These findings suggest that METH had pronounced effects on hormonal secretion during pregnancy, and hormonal transport to or hormonal production by the fetuses. In contrast, METH did not exhibit any adverse effects on the hormonal and cyclic nucleotide levels of pseudopregnant rats with deciduoma formation; a model for the maternal compartment. These latter findings may reflect METH's adverse effects on the fetal compartment, and suggest the use of pseudopregnancy as a model to distinguish adverse drug effects between these compartments.