Long-Term Voluntary Exercise and the Mouse Hypothalamic-Pituitary-Adrenocorticoid Axis: Impact of Concurrent Treatment with the Antidepressant Drug Tianeptine

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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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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

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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

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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

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

• Male C57BL/6N mice
• 10-12 weeks in age
• Singly housed
• 1212 h light/dark cycle
• Lights on 6.00 h

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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
• SSRIs (selective serotonin reuptake inhibitors)

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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

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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

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Groups

• Sedentary (S)
• Exercise (E)
• Antidepressant (A)
• Exercise Antidepressant (EA)

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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

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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

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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

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Killing process

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

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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
Hormonal assessment CRH ACTH Corticosterone Restraint Clear plastic tube 30 minute exposure Death trunk blood collected
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Wheel running Figure 1
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Liquid Intake figure 2
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Weight figure 3
Body Weight
Abdominal Fat
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Adrenal Glands - figure 4
Left Right Adrenal
Left Adrenal
Right Adrenal
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TH mRNA expression in adrenal medulla and locus
coeruleus figure 5
Adrenal Medulla
Locus coeruleus
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Baseline and Stress-induced plasma ACTH and
corticosterone levels - figure 6
ACTH
Corticosterone
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• E and EA decrease baseline levels of
  corticosterone
• E and EA decrease corticosterone response to
  novel environment
• BUT E and EA increase corticosterone response
  to restraint stress
• Figure 6
• CRH is decreased with exercise
• Would expect to see a decrease in ACTH
• But you dont, ACTH is unaffected
• Figures 6 7

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CRF mRNA expression in hypothalamic PVN figure 7
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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

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The End Have a Great Christmas Break!