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?