Transcript James Robertson

EXERCISE AND THE
ENDOCANNABINOID
SYSTEM
The Neurobiology of the Runner’s High
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
AEA
2-AG
THC
CBD
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
CANNABINOIDS
 Produced on leaves and flowers of C. sativa
 Resins on the glandular trichomes
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 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
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
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
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)
ENDOCANNABINOID SYNTHESIS
ENDOCANNABINOIDS
AND EXERCISE
 Are they related?
Endocannabinoids:
Exercise:
-Stress response physiology
-Analgetic effects
-Increase appetite
-Induce sleep
-Lighten mood
-Stress response physiology
-Suppress pain
-Increase appetite
Induce sedation
-Improves mood
 So… probably
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?
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
SPARLING ET AL., 2003
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???
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
HÖFELMANN ET AL., 2013
 Serotonergic system
 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?
HÖFELMANN ET AL., 2013
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
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
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
HÖFELMANN ET AL., 2013
Fig 3
HÖFELMANN
ET AL., 2013
Fig 2
HÖFELMANN ET AL., 2013
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
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
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
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
HILL ET AL,. 2012
FIGURE 1
HILL ET AL,. 2012
FIGURE 2
HILL ET AL,.
2012
FIGURE 3
HILL ET AL,.
2012
FIGURE 4
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
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????
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
SYNTHESIS – RAICHLEN ET AL,. 2012
SYNTHESIS – RAICHLEN ET AL,. 2012
THE BIG PICTURE, BRO