Transcript Wheel Runnin Alters Serotonin (5-HT) Transporter, 5

WHEEL RUNNING ALTERS
SEROTONIN (5-HT)
TRANSPORTER, 5-HT1A, 5-HT1B,
AND ALPHA1B-ADRENERGIC
RECEPTOR MRNA IN THE RAT
RAPHE NUCLEI
Greenwood et al 2005
DEPRESSION
Thought
to be an overall
decrease in serotonin
transmission through out the
central nervous system.
Antidepressants
are designed to
reverse this process.
RAPHE
 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

PREVIOUS WORK

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

WHAT WAS LOOKED AT
SEROTONIN TRANSPORTER (5-HTT)(SERT)
Reuptakes 5-HT
5-HTT
Pre-synapse
5-HT
SEROTONIN 1A & 1B RECEPTORS
(5-HT1A & 5-HT1B)
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
Alpha1B Adrenergic Receptor
(α1b ADR)

Coupled Gp-protein / IP3 / Ca++

Norepinephrine binds

Stimulates Raphe
Increases 5-HT output
5-HTT, 5-HT1A, 5-HT1B, Α1B-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?

WHY WERE THESE 4 THINGS
LOOKED AT?
 Estimated
that all 5HT neurons in
raphe contain these things
 All
of these things can modulate
serotonin transmission in the raphe
Changes
in
distance
and
weight
Dorsal Raphe Nucleus (DRN)
Median Raphe Nucleus (MR)
5-HTT
5-HT1A
5-HT1B
α1b-ADR
Seritonin transporter mRNA levels (5-HTT)
Relative 5-HTT
mRNA levels:
integrated
optical density
AS FAR AS
5HTT IS CONCERNED
See a decrease in
raphe mRNA
Alpha 1B Adrenergic Receptor levels (α1b-ADR)
Relative alpha
1b-ADR mRNA
levels: Integrated
optical density
Α1B-ADR (NE
RECEPTOR)
NE
systems are activated by
acute exercise
 From
The
locus ceruleus
increased NE levels may
down regulate receptors
Seritonin 1B Receptor levels (5-HT1B)
Relative 5-HT1B
mRNA levels:
Integrated
optical density
5-HT1B
5-HT1B AUTORECEPTOR
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-HT1A)
Relative 5-HT1A
mRNA levels:
Integrated
optical density
5-HT1A autoreceptor
 Increased


after running
More negative feedback
Opposite of antidepressant treatment
 Increased
AND decreased levels of 5-HT1A
have been seen in suicides or depressed
subjects

There’s more to this story
5-HT1A



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-HT1A increasing after 6 weeks may provide a
means of protection from LH

Possibly other depression models as well
FURTHER
INVESTIGATIONS
 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)