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

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

Journal of Neuroendocrinology Volume 18, pages 915-9252006

Known effects of exerciseKnown effects of exercisePositive 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 Known Effects of Antidepressants 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 Synergistic effects of exercise and antidepressant exercise and antidepressant drug 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 Aim of study - To investigate whether - To investigate whether voluntary exercise and antidepressant co-voluntary exercise and antidepressant co-treatment exert synergistic effects on the treatment exert synergistic effects on the mouse HPA axismouse HPA axis

Animals Animals

Male C57BL/6N mice 10-12 weeks in ageSingly housed 12:12 h light/dark cycle

◦Lights on 6.00 h

Drug TreatmentDrug TreatmentAntidepressent – 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 Dosage & Method of AdministrationAdministration20 mg/kg body weight per dayAdministered 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 Dosage & Method of AdministrationAdministrationCollected 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

GroupsGroupsSedentary (S)

Exercise (E)

Antidepressant (A)

Exercise + Antidepressant (E+A)

Voluntary exercise Voluntary exercise paradigmparadigm

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 Assessment of physical measuresmeasuresWeighed 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 Following experimental period: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 processKilling processAnaesthetized in a glass jar

◦Isoflurane vapourDecapitated immediately

following anesthesia exposureTrunk blood collected

WHAT WAS MEASURED

TYPE OF STRESS

PROCESS

Physical measurements and gene expression measurements

Adrenal size (total, R, L)

TH mRNA expression

BaselineNo stressor

Death

Tissues collected:

brainadiposethymusadrenal

Hormonal assessment

CRHACTH

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

CRHACTH

Corticosterone

Restraint Clear plastic tube

30 minute exposure

Death – trunk blood collected

Wheel running – Figure 1Wheel running – Figure 1

Liquid Intake – figure 2Liquid Intake – figure 2

Weight – figure 3Weight – figure 3

Body Weight Abdominal Fat

Adrenal Glands - figure 4Adrenal Glands - figure 4

Left Adrenal

Right Adrenal

Left + Right Adrenal

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

Locus coeruleus

Adrenal Medulla

Baseline Baseline and Stress-and Stress-induced induced plasma plasma ACTH and ACTH and corticosterocorticosterone levels - ne levels - figure 6figure 6

ACTH 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 CRF mRNA expression in hypothalamic PVN – figure 7hypothalamic PVN – figure 7

ConclusionConclusionConcurrent 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 EndThe End

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