Diazepam Treatment of Pregnant Rats Differentially Affects Interleukin‐1 and Interleukin‐2 Secretion in Their Offspring During Different Phases of Postnatal Development

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Abstract
Treatment of pregnant Long Evans rats with benzodiazepines was found to cause alterations in cellular immune responses in their offspring. We now report on changes in interleukin‐1 (IL‐1) and IL‐2 secretion which were analyzed in rats from birth until 12 weeks. Time‐pregnant rats were treated with diazepam (1.25 mg/kg/day subcutaneously) from gestational day 14 to 20. Lipopolysaccharide‐stimulated release of macrophage‐derived IL‐1 by spleen cells, determined on D10.G4.1 cells, remained in the control range during the preweaning period (postnatal day 6–28), then decreased in prenatally diazepam‐exposed offspring, significantly in males during the postweaning period (postnatal day 34–61) and in both sexes in adults (postnatal day 62–83). Concanavalin A‐stimulated release of T lymphocyte‐derived IL‐2 from spleen cells, determined on CTLL‐2 cells, was reduced in male and female offspring during preweaning (postnatal day 3–28) and postweaning (postnatal day 33–55) periods and normalized in adulthood (postnatal day 60–84). The percentage of IL‐2 receptor expressing (CD25+) cells was unaffected. From these and our earlier data it is evident that prenatal exposure to low doses of benzodiazepines can result in long‐lasting alterations of the cytokine network, as indicated by reduced release of TNF‐α, IL‐1, IL‐6, IL‐2 and interferon‐γ. The concomitant reduction of peripheral type benzodiazepine receptors on macrophages is discussed as a possible link between prenatal treatment and disturbed function.