EndocannabinoidsAn Emotional Buffer?
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
What are Endocannabinoids?
2 Primary Bioactive molecules
AEA = Anadamide
ArachidonylEthanolAmide
2AG = 2-ArachidonoylGlycerol
Many other less active forms Virodhamine, Nolandin Ether, NADA
HEA, DEA, PEA, OEA
Endocannabinoids (eCBs)
Endocannabinoid Structure
Comparison to Phytocannabinoids
AEA precursor = N-arachidonoyl
Phosphatidylethanolamine
Main Enzyme = NAPE-PLD N-acylphosphatidylethanolamine phospholipase D
Catabolic enzyme = FAAH (fatty acid amide hydrolase)
2-AG precursor = Diacylglycerol (DAG)
2nd Messenger: PLC →PIP2 → DAG → PKC
Main Enzyme = DAG Lipase Catabolic enzyme = MAG Lipase (monoacylglycerol Lipase)
eCB Synthesis/Breakdown
eCB Synthesis/Breakdown
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 1Nuclear Receptor: PPARs
Peroxisome proliferator-activated receptorsTransporters: EMT, FLAT
Mechanism of Action: Receptors
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
Mechanisms: CB1 Receptors
Rare pre & postsynaptic Neuronal Receptor Highly Inducible (100X) – Trauma, Anxiety
More CB2 on microglia
Binds 2-AG, AEA, Δ9THC
Triggers Gi/o protein → (functional selectivity)
→↓ AC/cAMP/PKA →↑ K+ channels, ↓Ca++ channels
→↑ MAPK →↑ PI3K/Akt (PKB)
Inhibits Glu or GABA release (44% homology to CB1)
Mechanisms: CB2 Receptors
eCB control of Glu/GABA release
The Endocannabinoids are RetrogradeMessengers
Therefore:
eCB control of Glu release
Widely expressed in Brain Lowers blood pressure?
Binds AEA, 2-AG, Δ9THC,CBD
Triggers G13α protein →
→↑[Ca++], ↑RhoA, Rac, Cdc42 (Ras GTPases)
→↑ pERK
Actin Cytoskeleton Remodeling
Mechanisms: CB3/GPR55
Receptors
Transient Receptor Potential cation channel subfamily V member 1 Located on Nociceptors, found in CNS
Binds capsaicin (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
Mechanisms: TRPv1 Channels
Peroxisome Proliferator-Activated Receptor Nuclear: genomic + rapid non-genomic
action Act as Transcription FactorsLong-lasting
Heterodimerize with Retinoid X Receptors
↑Tyrosine Kinases ↑Adiponectin/Lipoprotein Lipase
Opposite effects of CB1/2
Mechanisms: PPARs
Therapeutic Effects
I. AEA + 2-AG are Synthesized on Demand1.In Discrete Brain Areas
2.Depending oni. Nature and Intensity of Environmental Stimuli
II. CB1 + CB2 receptors are widely expressed
1.In Brain regions responding to Stressful Stimuli
i. May be opposite effects
ii. Depending on Anatomical Location
eCB Buffering and Homeostasis1
III. CB1 + CB2 are expressed presynaptically
1. Suppresses release of Glu + GABAi. Retrograde inhibition is Negative Feedback
III. CB2 relevant for emotional responses
IV. PPARs modulate aversive memory consolidation
V. TRPV1 mediate opposing emotional responses compared to CB1
1. Densities of eCB molecular componentsi. Differ between synapse types (Glu or GABA)
eCB Buffering and Homeostasis2
CB1/CB2 action on corticosterone
WIN55,212-2 = CB1 & CB2 receptor agonist
Novelty
Habituated to Novelty
Stress
No Stress
Therefore: The effect of Endocannabinoids can
beDirect IndirectSynergisticModified by Environmental ConditionsModified by Social Factors
AEA + 2-AG affect Stress Hormones
CB1/CB2 affects Learning
Stress
Stress
No Stress
No Stress
Influenced by Stress and Timing
Obje
ct R
eco
gnit
ion
Le
arn
ing
CB1/CB2 effect on Learning
depends on Corticosterone (B)
↓ [B] ↓ [B]
Obje
ct
Reco
gn
itio
n
Synergistic Actions
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
Do AEA/2-AG-CB1/CB2 act as buffers
against Environmental Stressors?
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