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
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. Physical measurements and gene expression measurements
WHAT WAS MEASURED
TYPE OF STRESS
PROCESS
Physical measurements and gene expression measurements
Adrenal size (total, R, L)
TH mRNA expression
Baseline
No stressor
Death
Tissues collected:
brain
adipose
thymus
adrenal
Hormonal assessment
CRH
ACTH
Corticosterone
Novel
New clean cage
30 minute exposure
½ control and ½ exercise groups provided with a clean running wheel
Death – trunk blood collected
Restraint
Clear plastic tube

16. Wheel running – Figure 1

17. Liquid Intake – figure 2

18. Weight – figure 3
Body Weight
Abdominal Fat

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

20. TH mRNA expression in adrenal medulla and locus coeruleus – figure 5

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

22. 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

23. CRF mRNA expression in hypothalamic PVN – figure 7

24. 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 glucocorticoid secretory output
Complex interactions of exercise, tianeptine, and stress coping

25. The End Have a Great Christmas Break!