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

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

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

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

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

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

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)

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

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

Groups Sedentary (S) Exercise (E) Antidepressant (A) Exercise + Antidepressant (E+A)

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

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

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

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

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

Wheel running – Figure 1

Liquid Intake – figure 2

Weight – figure 3 Body Weight Abdominal Fat

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

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

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

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

CRF mRNA expression in hypothalamic PVN – figure 7

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

The End Have a Great Christmas Break!