1. Exercise and the Endocannabinoid System
The Neurobiology of the Runner’s High

2. What are Cannabinoids? A diverse group of chemical compounds
Act upon cannabinoid receptors
Common across plants and animals
Synthetic Cannabinoids
Dronabinol (Marinol) – THC
Sativex (CBD. THC) – Therapeutic
Rimonabant (SR141716) – CB1 agonist
Anti-obesity, anti-smoking drug

3. AEA
THC
2-AG
CBD

4. Cannabinoids Name derived from Cannabis sativa L.
In use by H. sapiens since 5,000 BCE
Used as a drug since 1st-millenium BCE
“"The Scythians, as I said, take some of this hemp-seed [presumably, flowers], and, creeping under the felt coverings, throw it upon the red-hot stones; immediately it smokes, and gives out such a vapour as no Grecian vapour-bath can exceed; the Scyths, delighted, shout for joy.”
Herodotus, The Histories 440 BCE

5. Cannabinoids Produced on leaves and flowers of C. sativa
Resins on the glandular trichomes   
85 cannabinoid compounds have been isolated in C. sativa
Cannabinoids are well-known lipophilic molecules (hence pot-brownies)
Previously thought to act by altering membrane lipids
1964 – Chemical Structure of THC discovered
1974 – Structural selectivity of THC indicates drug-receptor interaction
1990 – Orphan G-protein coupled receptor (GPCR) identified, named CB1
1992 – Anandamide identified as endogenous ligand of CB1 receptor

6. Endocannabinoid System
Neuromodulatory chemicals, receptors and enzymes
Appetite
Pain
Mood
Memory
Modulates actions of Cannabis use
CB1 Receptor
Pre-synaptic inhibitor
Activated by AEA, 2-AG, THC (psychoactive)
CB2 Receptor
Primarily activated by 2-AG

7. Anandamide From Sanskrit word ‘ananda’: joy, bliss, delight
Modulates CB1 receptors in CNS
Feeding behavior
Pleasure
Motivation
CB2 Receptor – Periphery
Immune suppression
Cell migration
Implantation of blastocyst into uterine wall

8. Endocannabinoid Synthesis
Created in post-synaptic neurons in response to signaling
Breakdown of phospholipids of intra-cellular membranes
Increases intracellular Ca+
Exclusive synthesis (AEA/2-AG)

9. Endocannabinoid Synthesis

10. Endocannabinoids and exercise
Are they related?
So… probably
Endocannabinoids:
-Stress response physiology
-Analgetic effects
-Increase appetite
-Induce sleep
-Lighten mood
Exercise:
-Stress response physiology
-Suppress pain
-Increase appetite
Induce sedation
-Improves mood

11. Sparling et al., 2003 Exercise makes you feel good
Analgesia and Anxiolysis
Previously thought to be due to endorphins
Cannabinoid system reduces pain
Central and peripheral levels
Could exercise induced-analgesia be related?

12. Sparling et al., 2003 Experiment:
24 male college students
Consistent runners/cyclers
Running (8) Cycling (8) Sedentary (8)
45 minutes of exercise – moderate intensity
Blood collected pre and post-exercise
Measured for AEA levels

13. Sparling et al., 2003

14. Sparling et al., 2003 Elevated AEA in blood supports hypothesis
ECBs are the mechanism of exercise-induced analgesia
AEA is synthesized in peripheral sensory neurons
AEA  Nociception via peripheral pain-related CB1 receptors
What about the brain? Anxiolysis?
AEA crosses blood-brain barrier rapidly
THC acts on CNS CB1 receptors
Induces similar feelings to those experienced by endurance athletes
Perhaps increased AEA levels are accomplishing the same feat (perhaps)
But How???

15. Endocannabinoids and anxiety
Post-synaptic release of ECBs modulates presynaptic action
Short and long term scale
Memory modulation
Extinction of aversive memories
Endocannabinoids:
Stress response physiology
Analgetic effects
Increase appetite
Induce sleep
Lighten mood

16. Höfelmann et al., 2013 Serotonergic system Amygdala
Affects wide range of behaviors and emotional states
5-HT3 receptors modulate the release of several neurotransmitters
Antagonistic tests show inconsistent effects on anxiety
Suggests role of additional actors
Modulation of/by ECBs could explain contradictory results
Amygdala
Analgesia and emotional behavior
CB1 and 5-HT3 are co-localized in BLA
Synergy?

17. Höfelmann et al., 2013

18. Höfelmann et al., 2013
Experiment One: Serotonergic System and Fear Conditioning
Mice underwent Auditory Fear Conditioning
Measure freezing time after a loud stimulus
BLA dependent
Followed by administration of 5-HT3 receptor agonist (SR57227A)
5-HT3 activation impaired extinction of fear

19. Höfelmann et al., 2013
Experiment Two: Serotonergic System and Fear Conditioning
Mice pre-treated with 5-HT3 antagonist (Trop)
Mice underwent Auditory Fear Conditioning
Measure freezing time after a loud stimulus
BLA dependent
5-HT3 antagonist reduced expression of conditioned fear

20. Höfelmann et al., 2013
Experiment Three: Interaction of 5-HT3 and CB1receptors in Fear
Mice pre-treated with 5-HT3 antagonist (Trop)
And CB1 inversive agonist (Rim)
Mice underwent Auditory Fear Conditioning
Measure freezing time after a loud stimulus
BLA dependent
5-HT3 antagonist reduced expression of conditioned fear
CB1 agonist overruled these effects

21. Höfelmann et al., 2013
Fig 3

22. Höfelmann et al., 2013
Fig 2

23. Höfelmann et al., 2013

24. Höfelmann et al., 2013 No interaction between ECBs and 5-HT3 in BLA
LTDi was unaffected by 5-HT3 agonism/antagonism
CB1 and 5-HT3 receptors are tightly co-localized
Any interaction doesn’t come in this form of synaptic plasticity though
ECBS and Serotonergic Systems do not interact via GABA neurotransmission in the BLA
Not the mechanism of ECB anxiolysis

25. Hill et al,. 2012 Pyramidal neurons in the Amygdala
Primary output neurons
Suppression of BLA excitation reduces anxiety
Facilitation of excitation in BLA produces hypervigilance, anxiety
Chronic stress increases excitability, growth of pyramidal neurons in BLA
Likely mechanism in the development of anxiety
ECB in the BLA
Known to modulate stress
Contributes to synaptic plasticity

26. Hill et al,. 2012
What if mechanism of ECB action in BLA comes at a different point?
Does ECB act on anxiety in BLA via Fatty Acid Amid Hydrolase (FAAH)?
Known to be modulated by stress
Contributes to synaptic plasticity

27. Hill et al,. 2012 Experiment: FAAH Deficient Mice / Wild Type
Stress/Non Stress
Stress: 6hrs restraint for 21 days
Anxiety Test 24hrs after final restraint stress
Elevated Plus Maze
Open Field Test

28. Hill et al, Figure 1

29. Hill et al, Figure 2

30. Hill et al, Figure 3

31. Hill et al, Figure 4

32. Hill et al,. 2012 Chronic Stress increases action of FAAH
Decreases levels of AEA in tissue
No effect on CB1site density or affinity in Amygdala
Therefore, FAAH deficiency prevents dendritic arborization response
FAAH deficiency also prevents the promotion of anxiety behavior
EPM open-arm entries remain the same
FAAH represent likely mechanism of interaction between ECB and anxiety response

33. Ecbs, Exercise and anxiety where do we stand?
Hill 2012 points to a likely area for ECB System to interact with anxiety response in BLA
FAAH may be a target for treatment of anxiety disorders
Open questions:
How does the ECBS act to reduce anxiety?
What is the mechanism by which exercise activates the ECBS?
How on earth do I tie all of these disparate notions together????

34. Synthesis – Raichlen et al,. 2012
Goal-oriented behaviors with high energy costs
Motivated by neurological rewards
Conditions fitness enhancement
ECBS may or may not immediately impact anxiety system
But, rewarding the exercise effort could select for beneficial traits
Shown in other cursorial mammals

35. Synthesis – Raichlen et al,. 2012

36. Synthesis – Raichlen et al,. 2012

37. The Big Picture, Bro