w heel r unning a lters s erotonin (5-ht) t ransporter, 5-ht 1a, 5-ht 1b, and a lpha 1 b -a...
TRANSCRIPT
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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
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DEPRESSIONThought to be an overall decrease in serotonin transmission through out the central nervous system.
Antidepressants are designed to reverse this process.
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RAPHESerotonin output center of the
brainThought to be a big source of
action for SSRIsPrevents the reuptake of serotonin
increasing neurotransmissionTreats depression
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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
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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
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WHAT WAS LOOKED AT
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SEROTONIN TRANSPORTER (5-HTT)(SERT)
Pre-synapse
5-HT
5-HTT
Reuptakes 5-HT
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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
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Coupled Gp-protein / IP3 / Ca++
Norepinephrine binds
Stimulates Raphe Increases 5-HT output
Alpha1B Adrenergic Receptor
(α1b ADR)
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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
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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
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Changes in
distance and weight
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Dorsal Raphe Nucleus (DRN) Median Raphe Nucleus (MR)
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5-HTT 5-HT1A 5-HT1B α1b-ADR
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Seritonin transporter mRNA levels (5-HTT)
Relative 5-HTT mRNA levels: integrated optical density
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AS FAR AS 5HTT IS CONCERNED
See a decrease in raphe mRNA
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Alpha 1B Adrenergic Receptor levels (α1b-ADR)
Relative alpha 1b-ADR mRNA levels: Integrated optical density
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Α1B-ADR (NE RECEPTOR)
NE systems are activated by acute exerciseFrom locus ceruleus
The increased NE levels may down regulate receptors
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Seritonin 1B Receptor levels (5-HT1B)
Relative 5-HT1B mRNA levels: Integrated optical density
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5-H
T1B
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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)
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Relative 5-HT1A mRNA levels: Integrated optical density
Seritonin 1A Receptor levels (5-HT1A)
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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
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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
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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)