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Endocannabinoids

Explore the fascinating world of endocannabinoids, the lipid neuromodulators synthesized on demand, providing the framework for the mechanisms of actions for Cannabis sativa. Learn about the structure, synthesis/breakdown, receptors, and control of glutamate (Glu) release through CB1, CB2, and CB3/GPR55 receptors. Discover how PPARs and TRPV1 channels play a role in emotional responses and how endocannabinoids act as buffers against environmental stressors, shaping our emotional memory and behavior.

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Endocannabinoids

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  1. Endocannabinoids An Emotional Buffer?

  2. What are Endocannabinoids? • Lipid neuromodulators and hormones • Made from Membrane phospholipids • Synthesized On Demand • stimulated production • Provide the Framework (receptors etc) for • the mechanisms of actions for • Cannabis sativa

  3. Endocannabinoids (eCBs) • 2 Primary Bioactive molecules • AEA = Anadamide • ArachidonylEthanolAmide • 2AG = 2-ArachidonoylGlycerol • Many other less active forms • Virodhamine, Nolandin Ether, NADA • HEA, DEA, PEA, OEA

  4. Endocannabinoid Structure

  5. Comparison to Phytocannabinoids

  6. eCB Synthesis/Breakdown • AEAprecursor = N-arachidonoyl Phosphatidylethanolamine • Main Enzyme = NAPE-PLD • N-acylphosphatidylethanolamine phospholipase D • Catabolic enzyme = FAAH (fatty acid amide hydrolase) • 2-AGprecursor = Diacylglycerol (DAG) • 2nd Messenger: PLC →PIP2→DAG→ PKC • Main Enzyme =DAG Lipase • Catabolic enzyme = MAG Lipase (monoacylglycerol Lipase)

  7. eCB Synthesis/Breakdown

  8. Mechanism of Action: Receptors • Cannabinoid Receptors: 2 classic + 1 or 2 • CB1: high density in central nervous system • CB2: low density in CNS; high peripherally • GPR55: CB3 – but another CB3 in hippocampus • Cationic Channel Vanilloid Receptor: TRPV1 • Transient Receptor Potential – Vanilloid 1 • Nuclear Receptor: PPARs • Peroxisome proliferator-activated receptors • Transporters: EMT, FLAT

  9. Mechanisms: CB1Receptors • High density Neuronal Receptor • Presynaptic on GABA and Glu neurons • Lipid raft microdomains - concentrating • Binds AEA, 2-AG, Δ9THC • Triggers Gi/o protein → • →↓ AC/cAMP/PKA →↑ K+channels,↓Ca++channels • →↑ MAPK →↑ ERK , p38 • Inhibits Glu or GABA release

  10. Mechanisms: CB2Receptors • Rarepre & postsynaptic Neuronal Receptor • Highly Inducible (100X) – Trauma, Anxiety • More CB2 on microglia • Binds 2-AG, AEA, Δ9THC • Triggers Gi/oprotein → (functional selectivity) • →↓ AC/cAMP/PKA →↑ K+channels,↓Ca++channels • →↑ MAPK →↑ PI3K/Akt(PKB) • Inhibits Glu or GABA release (44% homology to CB1)

  11. eCB control of Glu/GABA release

  12. Therefore: The Endocannabinoids are RetrogradeMessengers

  13. eCB control of Glu release

  14. Mechanisms: CB3/GPR55Receptors • Widelyexpressed in Brain • Lowers blood pressure? • Binds AEA, 2-AG, Δ9THC,CBD • Triggers G13α protein → • →↑[Ca++], ↑RhoA, Rac, Cdc42 (Ras GTPases) • →↑ pERK • Actin Cytoskeleton Remodeling

  15. Mechanisms: TRPv1 Channels • Transient Receptor Potential cation channel subfamily V member 1 • Located on Nociceptors, found in CNS • Bindscapsaicin (jalapeño, habanero), allyl isothiocyanate(wasabi) • Binds 2-AG,AEA,Δ9THC • Also opened by acid, T° > 43°C(109°F) • →↑[Ca++] • →↑ Caspases, Cytochrome C release, mitochondrial uncoupling, Pro-apoptosis Kinases • Sensation of Scalding Heat and Pain

  16. Mechanisms: PPARs • Peroxisome Proliferator-Activated Receptor • Nuclear: genomic + rapid non-genomic action • Act as Transcription Factors • Long-lasting • Heterodimerize with Retinoid X Receptors • ↑Tyrosine Kinases • ↑Adiponectin/Lipoprotein Lipase • Opposite effects of CB1/2

  17. Therapeutic Effects

  18. eCB Buffering and Homeostasis1 • AEA + 2-AG are Synthesized on Demand • In Discrete Brain Areas • Depending on • Nature and Intensity of Environmental Stimuli • CB1 + CB2receptors are widely expressed • In Brain regions responding to Stressful Stimuli • May be opposite effects • Depending on Anatomical Location

  19. eCB Buffering and Homeostasis2 • CB1+ CB2are expressed presynaptically • Suppresses release of Glu + GABA • Retrogradeinhibition is Negative Feedback • CB2 relevant for emotional responses • PPARsmodulate aversive memory consolidation • TRPV1mediate opposing emotional responses compared to CB1 • Densities of eCB molecular components • Differ between synapse types (Glu or GABA)

  20. CB1/CB2 action on corticosterone Stress No Stress Novelty Habituated to Novelty WIN55,212-2 = CB1 & CB2 receptor agonist

  21. AEA + 2-AG affect Stress Hormones • Therefore: • The effect of Endocannabinoids can be • Direct • Indirect • Synergistic • Modified by Environmental Conditions • Modified by Social Factors

  22. CB1/CB2affects Learning Stress Stress No Stress No Stress Object Recognition Learning Influenced by Stress and Timing

  23. CB1/CB2effect on Learningdepends onCorticosterone (B) Object Recognition ↓ [B] ↓ [B]

  24. Synergistic Actions

  25. Do AEA/2-AG-CB1/CB2act as buffers againstEnvironmental Stressors? • Inhibit Short-term Learning • Enhance Long-term Learning • During Stressful Conditions • Modify the Effects of Stress Hormones • Stimulated/modified by stress hormones • Moderate Environmental Impacts • on Emotional Memory • Attenuate Excessive Behavioral Responses

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