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

DEPRESSIONThought to be an overall decrease in serotonin transmission through out the central nervous system.

Antidepressants are designed to reverse this process.

RAPHESerotonin output center of the

brainThought to be a big source of

action for SSRIsPrevents the reuptake of serotonin

increasing neurotransmissionTreats 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)

Pre-synapse

5-HT

5-HTT

Reuptakes 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

Coupled Gp-protein / IP3 / Ca++

Norepinephrine binds

Stimulates Raphe Increases 5-HT output

Alpha1B Adrenergic Receptor

(α1b ADR)

5-HTT, 5-HT1A, 5-HT1B, Α1B-ADR

In situ hybridization Measures mRNA

levels Assumed there is a

direct correlation with protein

Translation? Binding to

receptors?

What technique was used? Problems with this technique

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 exerciseFrom locus ceruleus

The increased NE levels may down regulate receptors

Seritonin 1B Receptor levels (5-HT1B)

Relative 5-HT1B mRNA levels: Integrated optical density

5-H

T1B

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)

Relative 5-HT1A mRNA levels: Integrated optical density

Seritonin 1A Receptor levels (5-HT1A)

5-HT1A autoreceptor Increased after running

More negative feedbackOpposite of antidepressant treatment

Increased AND decreased levels of 5-HT1A have been seen in suicides or depressed subjectsThere’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 antidepressants6 wks but not 3wks of running

overcomes learned helplessness in shuttle box (Greenwood)