Download - Greenwood et al 2005
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)