Abstract
Oxytocin (OXT), synthesized in the hypothalamic paraventricular nucleus (PVN) and then released into different brain areas, may play a crucial role in various behaviors and neuropsychiatric disorders, including depression. Testosterone has been proposed by clinical studies to have the opposite effect of oxytocin in these disorders. We began by studying, in the postmortem hypothalamus of fifteen patients with mood disorders and fifteen matched controls, the expression of OXT in the PVN by means of immunocytochemistry (ICC) and the co-localization of OXT and androgen receptor (AR) by means of double labeling ICC. Subsequently, the regulatory effect of AR on OXT gene expression was studied in vitro. We found a higher expression of PVN OXT in the mood disorder patients than in the control subjects, and observed a clear co-localization of AR in OXT-expressing neurons, both in the cytoplasm and in the nucleus. In addition, a significant decrease in OXT-mRNA levels was observed after pre-incubation of the SK-N-SH cells with testosterone. A further potential androgen-responsive element in the human OXT gene promotor was revealed by electrophoretic mobility shift assays and co-transfections in neuroblastoma cells. Finally, in vitro studies demonstrated that AR mediated the down-regulation of OXT gene expression. These results suggest that the fact that OXT and testosterone appear to have opposite effects in neuropsychiatric disorders might be based upon a direct inhibition of AR on OXT transcription, which may provide a novel target for therapeutic strategies in depression.
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Acknowledgements
We are grateful to the Netherlands Brain Bank (Director Dr Inge Huitinga) for providing human brain material and clinical details, to Professor Joost Verhaagen for critically reading the manuscript, to Dr F.W. van Leeuwen for providing the OXT antibody, to Dr J. Trapman for providing the plasmid PSV-AR and to Ms W.T.P. Verweij for her secretarial assistance.
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Dai, D., Li, QC., Zhu, QB. et al. Direct Involvement of Androgen Receptor in Oxytocin Gene Expression: Possible Relevance for Mood Disorders. Neuropsychopharmacol 42, 2064–2071 (2017). https://doi.org/10.1038/npp.2017.76
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DOI: https://doi.org/10.1038/npp.2017.76
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