Week 5 part 2 Flashcards
What was opioid receptor discovery in 1970 for?
Targets for morphine and heroin
What did targets for morphine and heroin lead to?
Discovery of neuropeptide (enkephalins and endorphins) as endogenous ligands for these receptors
What did discovery of cannabinoid receptors in the late 1980’s suggest
endogenous ligands for these receptors may be produced in the brain
What may endogenous cannabinoid receptor ligands be?
neuropeptides
What were neuropeptides shown to be?
Ligand for opioid receptors
Where was the first endogenous cannabinoid receptor isolated from?
Brain
Identified as a derivative of fatty acid arachnoid acid
What was endogenous cannabinoid receptor ligand purified from?
brain extract as a compound that binds to cannabinoid receptors
What is the first endogenous cannabinoid receptor ligand named chemically
- arachidonoylethanolamide
2. Known as anandamide
in 1995, what was the secind endogenous cannabinoid receptor ligand identified as?
2-arachidonoylglycerol
Named as arachidonoylglycerol
Why is anandamide and 2AG structurally similar?
They are derivatives of arachnoid acid
What do anandamide and 2AG act as?
endogenous ligands for cannabinoid receptors CB1 and CB2
What can anandamide and 2AG be traced back to?
common ancestor of caudate which will take u back ½ a billion years
What is the evolutionary origin of the cannabis plant?
50 million years
What is cannabinoid receptors in the brain?
At least 10 times older than THC is
Where is 2AG synthesised ?
In the brain via a specific pathway
What is now recognized as the enzyme primarily responsible for biosynthesis of 2-AG in the brain?
• DGL or DAGL, diacylglycerol lipase
What is the substrate for the enzyme DAG-lipase which then generates 2AG from this precursor molecules
• 1-2 DAG
what are two types of DAGL in mammalian brain?
DAGL-alpha and DAGL-beta
What do most neurotransmitter systems have?
mechanism of inactivation
What is anandamide converted to?
Arachidonic acid and ethanolamide by an enzyme known as fatty acid amide hydrolase (FAAH)
What is 2-AG converted to?
arachidonic acid and glycerol
by an enzyme known as monoacylglycerol lipase (MAGL)
What are inhibitors of FAAH and MAGL being investigated as?
potential drugs for treatment of a variety of neurological disorders
What does THC have beneficial effects on?
Analgesia
how can you selectively increase endogenous cannabidiols in different parts of brain to different extent?
inhibiting the enzymes generate endogenous cannabinoids
What do endocannabinoid act as ?
synaptic retrograde messenger molecules
What is not present in purjinke cells?
CB1
What are presynaptic to purjinke cells?
CB1
What are post-synaptic to purijnke cells?
FAAH
What is the retrograde signalling system?
endocannabinoids maybe be synthesized post synaptically and then acting presynaptically
Why do endocannabinoid act backwards across synapse?
Acting as a mechanism to inhibit release of neurotransmitter presynatpically based on the information presented early on
What does post-synaptic cell make ?
Anandamide
What does CB1 receptor use?
GPCR reduce CAMP and decrease ca2+ permeability and inhibit neurotransmitter release
What do purkinje cells have?
extensive dendritic tree
Through the dendritic tree parallel fibres pass through and contact dendritic tree
What do small parallel fibre depolarise?
small aspect of the dendritic tree
What does Endocanabinoid mediate?
CB1-dependent depolarisation
What is abolished in CB1-knock out mice?
DSI and DSE
What do endocannabinoid also mediate?
CB1-dependent long-term depression of excitatory and inhibitory neurotransmission
What is primarily responsible for mediating endocannabinoid-mediated retrograde signalling at synapses in the brain?
2-AG
What is 2-AG doing
mediating depolarisation induced suppression of synaptic transmission
