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Dexamethasone nonsuppression in transgenic mice expressing antisense RNA to the glucocorticoid receptor
1Max Planck Institute of Psychiatry, Department of Neuroendocrinology, Munich, Germany.
Abstract:
Transgenic mice with impaired glucocorticoid receptor (GR) function produced by partially knocking out GR gene expression with antisense RNA were treated with increasing dosages of dexamethasone. In these mice, ten-fold higher dexamethasone dosages were required to induce full suppression of plasma corticosterone than in normal mice. This relative dexamethasone insensitivity adds to the evidence that these transgenic mice could serve as an appropriate model to study the negative feedback disturbance of the hypothalamic-pituitary-adrenocortical system in affective disorders.
Insights
Transgenic mice with impaired glucocorticoid receptor (GR) function showed reduced sensitivity to dexamethasone. These mice offer a model for studying hypothalamic-pituitary-adrenal axis disruptions in affective disorders.
Area of Science:
- Neuroendocrinology
- Molecular Biology
- Genetics
Background:
- The hypothalamic-pituitary-adrenal (HPA) axis regulates stress response, and its dysregulation is implicated in affective disorders.
- Glucocorticoid receptor (GR) plays a crucial role in the negative feedback of the HPA axis.
- Understanding GR function is vital for modeling HPA axis disturbances.
Purpose of the Study:
- To characterize dexamethasone response in transgenic mice with impaired glucocorticoid receptor (GR) function.
- To evaluate the utility of these mice as a model for studying HPA axis negative feedback disturbances relevant to affective disorders.
Main Methods:
- Generation of transgenic mice with partially reduced GR gene expression using antisense RNA.
- Administration of increasing dexamethasone dosages to transgenic and normal mice.
- Measurement of plasma corticosterone levels to assess dexamethasone's suppressive effect.
Main Results:
- Transgenic mice required ten-fold higher dexamethasone dosages for full plasma corticosterone suppression compared to normal mice.
- This indicates a relative dexamethasone insensitivity in mice with impaired GR function.
- The findings support the functional impairment of the GR-mediated negative feedback loop.
Conclusions:
- Transgenic mice with impaired GR function exhibit dexamethasone insensitivity.
- These mice represent a valuable model for investigating HPA axis negative feedback disruptions in affective disorders.
- Further research using this model can elucidate the role of GR in the pathophysiology of mood disorders.