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 THC 2-AG 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    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? 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

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 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?

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