Lecture 22; Endocannabinoids Flashcards by Calum Macindoe

What is the pot plant?

Cannibis sativa

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What is the psycho active substance in POT and what does it do?

–Psychoactive compound Δ9-THC
–hunger
–mood
•Euphoria/anxiety
–other effects

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What are the principle endocannabinoids in the brain?

2-AG and Anandamide

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What are the major cannabinoid receptors?

CB1
CB2
GPR18,55 and 115

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Write some notes on CB1;

1.Cannabinoid Receptor 1 (CB1)
•Widely expressed in CNS
•Presynaptic localization (effects neurotransmission)
•Involved in modulation of synaptic transmission–our focus

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Write some notes on CB2;

2.CB2
•Expressed in immune cells
•Not involved in synaptic transmission
•Low expression in CNS

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Write some notes on GPR18,55, and 115

3.GPR18, 55 & 115
•Protein/gene sequence homology
•Activated by endo-(and exo-) cannabinoids
•Unknown involvement in synaptic transmission

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Describe CB1 structure;

7 TMS
Gi/o coupled

inhibits adenylate cyclase, lowers cAMP and increases MAP kinase

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What is the result of CB1 lower cAMP levels?

Net effect of K+and Ca2+channel changes is less Ca2+entry and therefore less neurotransmitter release –CB1 activation inhibits neurotransmitter release

shortens duration of action potential arriving at the synapse.

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What is a partial agonist of CB1?

Anandamide

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How is andandamide produced?

N-acyltransferase (NAT) -> (NAPE-PLD) -> AEA
NAT is Ca2+-dependent

Metabolised by FAAH

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What is anandamide a full agonist of?

TRPV1 has opposing effects of CB1

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What produces 2AG?

PLC and DGL(a)

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What is 2AG metabolised by?

MGL

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What are some other endocannabinoids?

NADA

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Describe how endocannbinoids function?

GABAergic transmission (IPSC amplitude) reduced after depolarizing the post-synaptic neuron

A retrograde mechanism whereby post-synapticactivity (depolarization) effects pre-synaptic neurotransmitter release

What is endocannbinoids transmission known as?

Depolarisation induced Suppression of inhibition

What are the mechanisms of eCB release?

Calcium driven eCB Release (CaER)
Receptor-driven eCB Release (basal-RER)
Calcium-assisted RER (CaRER)

Describe calcium drive eCB release;

Strongpost-synaptic depolarization•e.g. DSI protocol
Elevated post-synaptic Ca2+inhibits neurotransmitter release
2-AG mediated
Ca2+-dependent synthesizing enzymes
Blocked by Ca2+chelators

Describe receptor driven eCB release;

StrongG-protein coupled receptors (Gq/11-coupled) activation
Group I mGluRs(mGluR1 & mGluR5), M1 & M3 muscurinic, oxytocin, orexin, glucocorticoid
Independent of post-synaptic Ca2+ (basal Ca2+level)
Ca2+chelatorBATPA resistant
2-AG mediated
PLCβactivated by Gq/11-coupled receptors

Describe Ca assisted RER;

•Basal-RER enhanced by elevated post-synaptic Ca2+•PCLβactivity is Ca2+dependent•Synergistic effect of Ca2+and receptor activation on eCBproduction

What are the key features of the eCB system?

Retrograde action
Endocannabinoids produced on-demand
Function (primary): Modulation of synaptic transmission

Describe how eCB have retrograde action;

Produced in post-synaptic neuron (various mechanisms…see previous slides)
Activate CB1 receptor on pre-synaptic terminal

Describe how endocannabinoids are produced on demand;

Not stored in vesicles (like conventional neurotransmitters)
2-AG and anandamide are the principle endocannabinoids
We are also interested in NADA
Several mechanisms of production (CaER, basal RER, Ca2+assisted RER)

Describe CB1 primary function;

* CB1 activation inhibits neurotransmitter release (K+and Ca2+channels involved) * DSI: Post-synaptic depolarization leads to eCB production/release and inhibition of pre-synaptic neurotransmitter release

Describe the symptoms of parkinsons disease;

* Mainly motor-symptoms–Shaking, rigidity, slowness of movement * Also non-motor symptoms–Loss of sense of smell, disturbed sleep, constipation–Interesting: could precede motor-symptoms

Describe the pathology of parkinsons

–Loss of dopamine-producing neuronsin the substantia nigra pars compacta Loss of dopamine in the striatum Motor Symptoms

What is the current treatment for parkinsons?

L DOPA Brain adapts though side effects; •Dyskinesias –involuntary (tics/chorea)

Whats an alternative to L DOPA?

•Deep Brain Stimulation (DBS)–Neurosurgical technique–Silences overactive Subthalamic nucleus(STN)–Electrical stimulating electrode placed into the Subthalamic nucleus (or GPe)

Could endocannabinoids be a good target for parkinsons treatment?

eCBs indirectly modulate normal synaptic transmission Dopamine-neuron specific endocannabinoid NADA Some evidence for improved motor function and effectiveness of L-DOPA –mixed clinical results CB1 expression is high in the SNc

What is the potential for eCB in PD treatment?

1. Slow/stop disease progress | 2. Improve existing treatments (L-DOPA)

How many marajuana users are dependant?

10%