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S. K. Droste , M. C. Schweizer , S. Ulbrich , and J. M. H. M. Reul

Long-Term Voluntary Exercise and the Mouse Hypothalamic-Pituitary- Adrenocorticoid Axis: Impact of Concurrent Treatment with the Antidepressant Drug Tianeptine. S. K. Droste , M. C. Schweizer , S. Ulbrich , and J. M. H. M. Reul Journal of Neuroendocrinology Volume 18, pages 915-925 2006.

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S. K. Droste , M. C. Schweizer , S. Ulbrich , and J. M. H. M. Reul

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  1. Long-Term Voluntary Exercise and the Mouse Hypothalamic-Pituitary-Adrenocorticoid Axis: Impact of Concurrent Treatment with the Antidepressant Drug Tianeptine S. K. Droste, M. C. Schweizer, S. Ulbrich, and J. M. H. M. Reul Journal of Neuroendocrinology Volume 18, pages 915-925 2006

  2. Known effects of exercise • Positive effects on the brain • Decreases depression and anxiety • increased neurogenesis in Hc • Increased growth factors (IGF-1, BDNF) • Role of glutamate • Changes in the HPA axis • Decreased HPA sensitivity • Increased stress coping • Improved sleep quality

  3. Known Effects of Antidepressants • Increased neurogenesis in the dentate gyrus • Role of glutamate • Affects the HPA axis similar to exercise • decreased stress response • decrease in anxiety-related behavior • Improved sleep quality • Normalization of the HPA axis function

  4. Synergistic effects of exercise and antidepressant drug • BDNF expression in the hippocampus • Many overlapping effects • Suggested beneficial effects of exercise on the clinical course of antidepressant-treated patients

  5. Aim of study - To investigate whether voluntary exercise and antidepressant co-treatment exert synergistic effects on the mouse HPA axis

  6. Animals • Male C57BL/6N mice • 10-12 weeks in age • Singly housed • 12:12 h light/dark cycle • Lights on 6.00 h

  7. Drug Treatment • Antidepressent – Tianeptine • Shown to regulate neuroplasticity • Stimulate uptake of serotonin in cortex and hippocampus • Same effects on depression treatment as: • TCA (tricyclic antidepressant) and • SSRI’s (selective serotonin reuptake inhibitors)

  8. Dosage & Method of Administration • 20 mg/kg body weight per day • Administered in drinking water • Prevent a non specific stress effect in response to a series of injections • Dark water bottles • prevent the light sensitive tianeptine from breaking down

  9. Dosage & Method of Administration • Collected liquid intake over a 24 hour period (done twice a week) • Calculated a mean liquid intake for each week and mouse (ml/day) • [tianeptine] in drinking water adjusted throughout experiment • Compensate for changes in weight and liquid intake • The control group of mice got tap water

  10. Groups • Sedentary (S) • Exercise (E) • Antidepressant (A) • Exercise + Antidepressant (E+A)

  11. Voluntary exercise paradigm • Habituation to the housing conditions- 5 days • “E” and “E + A” had free access to running wheel in their home cages for 4 weeks • At this time antidepressant treatment began • Mice ran mainly during the first half of the dark phase of the diurnal cycle • Housing conditions of “A” and “S” remained unchanged

  12. Assessment of physical measures • Weighed weekly • Only tissues of mice killed under baseline conditions (7-9am) were collected for physical and gene expression measures • Tissues collected included: • Brain, Adipose, Thymus, Adrenal

  13. Following experimental period: • Exposed to a novel environment, or • Placed in a single clean cage with new sawdust and no food and water for 30 minutes • Extra variable: half control and exercise mice were provided with a clean running wheel in the new cage • Check for impact of novel environment on different groups • Restraint stress procedure. • Placed in a clear plastic tube for 30 minutes • Hormones assessed from trunk blood

  14. Killing process • Anaesthetized in a glass jar • Isoflurane vapour • Decapitated immediately following anesthesia exposure • Trunk blood collected

  15. Wheel running – Figure 1

  16. Liquid Intake – figure 2

  17. Weight – figure 3 Body Weight Abdominal Fat

  18. Adrenal Glands - figure 4 Left + Right Adrenal Left Adrenal Right Adrenal

  19. TH mRNA expression in adrenal medulla and locus coeruleus– figure 5 Adrenal Medulla Locus coeruleus

  20. ACTH Corticosterone Baseline and Stress-induced plasma ACTH and corticosterone levels - figure 6

  21. E and E+A decrease baseline levels of corticosterone • E and E+A decrease corticosterone response to novel environment • BUT… E and E+A increase corticosterone response to restraint stress • Figure 6 • CRH is decreased with exercise • Would expect to see a decrease in ACTH • But you don’t, ACTH is unaffected • Figures 6 & 7

  22. CRF mRNA expression in hypothalamic PVN – figure 7

  23. Conclusion • Concurrent long-term voluntary exercise and tianeptine treatment exert a potent action on the mouse HPA axis • Strongest impact on the adrenal gland • Synergistic action affecting adrenal structure and function • Mechanisms at the adrenal level are key in modulating glucocorticoidsecretory output • Complex interactions of exercise, tianeptine, and stress coping

  24. The EndHave a Great Christmas Break!

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