Lecture 22; Endocannabinoids Flashcards
What is the pot plant?
Cannibis sativa
What is the psycho active substance in POT and what does it do?
–Psychoactive compound Δ9-THC –hunger –mood •Euphoria/anxiety –other effects
What are the principle endocannabinoids in the brain?
2-AG and Anandamide
What are the major cannabinoid receptors?
CB1
CB2
GPR18,55 and 115
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
Write some notes on CB2;
2.CB2
•Expressed in immune cells
•Not involved in synaptic transmission
•Low expression in CNS
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
Describe CB1 structure;
7 TMS
Gi/o coupled
- inhibits adenylate cyclase, lowers cAMP and increases MAP kinase
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.
What is a partial agonist of CB1?
Anandamide
How is andandamide produced?
- N-acyltransferase (NAT) -> (NAPE-PLD) -> AEA
- NAT is Ca2+-dependent
Metabolised by FAAH
What is anandamide a full agonist of?
TRPV1 has opposing effects of CB1
What produces 2AG?
PLC and DGL(a)
What is 2AG metabolised by?
MGL
What are some other endocannabinoids?
NADA
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?
- Slow/stop disease progress
2. Improve existing treatments (L-DOPA)
How many marajuana users are dependant?
10%
