Transcript Carin Martinson

Long-Term Voluntary Exercise and
the Mouse Hypothalamic-PituitaryAdrenocorticoid 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 antidepressanttreated 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

WHAT WAS
MEASURED
TYPE OF
STRESS
PROCESS
Physical measurements
and gene expression
measurements
Baseline
No stressor
Death
brain
adipose
thymus
adrenal
Adrenal size (total, R, L)
TH mRNA expression
Hormonal assessment
Tissues collected:
Novel
New clean cage
30 minute exposure
CRH
ACTH
Corticosterone
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
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
Adrenal
Medulla
Locus
coeruleus
ACTH
Baseline and
Stress-induced
plasma ACTH
and
corticosterone
levels - figure 6
Corticosterone
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!