1. 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

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

3. 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

4. P REVIOUS W ORK 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

5. 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

6. W HAT WAS LOOKED AT

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

8. S EROTONIN 1A & 1B RECEPTORS (5-HT 1A & 5-HT 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

9. Coupled G p -protein / IP 3 / Ca ++ Norepinephrine binds Stimulates Raphe Increases 5-HT output Alpha1B Adrenergic Receptor ( α 1b ADR)

10. 5-HTT, 5-HT1A, 5-HT1B, Α 1 B -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

11. W HY 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

12. Changes in distance and weight

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

14. 5-HTT5-HT 1A 5-HT 1B α 1b -ADR

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

16. A S FAR AS 5HT T IS CONCERNED See a decrease in raphe mRNA

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

18. Α 1 B -ADR (NE RECEPTOR ) NE systems are activated by acute exercise From locus ceruleus The increased NE levels may down regulate receptors

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

20. 5-HT 1B

21. 5-HT 1B A UTORECEPTOR 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)

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

23. 5-HT 1A autoreceptor 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

24. 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

25. F URTHER 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)