W HEEL R UNNING A LTERS
S EROTONIN (5-HT)
T RANSPORTER , 5-HT
1A
, 5-HT
1B
,
AND A LPHA
1 B
-A DRENERGIC
R ECEPTOR M RNA IN THE R AT
R APHE N UCLEI
Greenwood et al 2005

D

Thought to be an overall decrease in serotonin transmission through out the central nervous system.

Antidepressants are designed to reverse this process.

R
APHE

Serotonin output center of the brain

Thought to be a big source of action for SSRIs


Prevents the reuptake of serotonin increasing neurotransmission
Treats depression


Voluntary wheel running acts as an antidepressent in models

Forced swim


Chronic mild stress
Learned helplessness

6 weeks wheel running lowers the activity of 5HT neurons in the dorsal raphe nucleus (DRN) during uncontrollable stress

Prevents learned helplessness

M&M

Male Fischer F344 rats individually housed

12:12hr light/dark cycle

Lights on at 6AM


1wk acclimatization with locked running wheels
Ad libitum food and water

Unlocked wheels for 3 days, 3 wks, 6wks

W

S EROTONIN T RANSPORTER (5-HT
T
)(SERT)
Reuptakes 5-HT
5-HT
T
Pre-synapse
5-HT

EROTONIN
RECEPTORS
1A
1B

Located on soma, dendrites and axon terminals

Act as auto receptors that inhibit:

Synthesis of 5-HT

Release of 5-HT

Ultra short loop negative feedback

(
1b
ADR)

Coupled G p
-protein / IP
3
/ Ca ++

Norepinephrine binds

Stimulates Raphe Increases 5-HT output

5-HTT, 5-HT1A, 5-HT1B,
Α
1 B -ADR
What technique was used?

In situ hybridization


Measures mRNA levels
Assumed there is a direct correlation with protein
Problems with this technique

Translation?

Binding to receptors?

W
4
?

Estimated that all 5HT neurons in raphe contain these things

All of these things can modulate serotonin transmission in the raphe

Dorsal Raphe Nucleus (DRN)
Median Raphe Nucleus (MR)

5-HTT 5-HT
1A
5-HT
1B
α
1b
-ADR

Seritonin transporter mRNA levels (5-HT
T
)
Relative 5-HTT mRNA levels: integrated optical density

S FAR AS
T IS CONCERNED
See a decrease in raphe mRNA

Alpha 1B Adrenergic Receptor levels ( α
1b
-ADR)
Relative alpha
1b-ADR mRNA levels: Integrated optical density

1 B

NE systems are activated by acute exercise

From locus ceruleus

The increased NE levels may down regulate receptors

Seritonin 1B Receptor levels (5-HT
1B
)
Relative 5-HT
1B mRNA levels:
Integrated optical density

5-HT
A

Trend of decreasing overall



Exercise and SSRIs decrease
Ventral DRN did show a significant decrease

Selective innervations of certain areas?


Caudate putamen
Cortex
In a separate study, increased 1B makes rats more anxiety prone
 suggests an increased capacity to synthesize presynaptic 5-HT1B receptors and could account for diminished serotonin neurotransmission in learned helplessness (Neumaier JF, et al)

Seritonin 1A Receptor levels (5-HT
1A
)
Relative 5-HT
1A mRNA levels:
Integrated optical density

5-HT

Increased after running


More negative feedback
Opposite of antidepressant treatment

Increased AND decreased levels of 5-HT
1A have been seen in suicides or depressed subjects

There’s more to this story

5-HT
1A

Learned helplessness(LH) appears to be dependent on hyperactivation and sensitization of DRN 5-HT neurons. (Takase et al)

LH can also be attenuated by 6wks voluntary wheel running (greenwood)

5-HT
1A increasing after 6 weeks may provide a means of protection from LH

Possibly other depression models as well

F

Interesting correlation between the time dependent effects of both running and antidepressants

6 wks but not 3wks of running overcomes learned helplessness in shuttle box (Greenwood)