Cannabinoids Flashcards
endocannabinoids
anandamide (AEA) and 2-arachidonylglycerol (2-AG)
- released into synaptic cleft and bind CB1 and CB2 receptors on the PRESYNAPTIC axon terminal
Anandamide
AEA
- synthesized from NAPE by NAPE phospholipase D in the postsynaptic neuron
- metabolized by fatty acid amide hydrolase (FAAH) to ethanolamine and arachidonic acid in POSTsynaptic neuron
2-arachidonylglycerol
2-AG
- also synthesized in post-synaptic neuron by diacylglycerol lipase (DAGL)
- metabolized by monoacylglycerol lipase (MAGL) in the presynaptic neuron
CB1R
- where
- what signalling cascades are linked
- main cannabinoid receptor
- found on many different presynaptic neurons (not just GABAergic) and also on mitochondrial membrane
- Biased signalling occurs - different conformation of the receptor and thus diff signalling depending on ligand:
- beta arrestin 1 pathway leading to late activation of ERK1/2 (kinase)
- g-protein pathway (Gi) which leads to reduced AC activity and less cAMP, and reduced calcium influx (VGCC) and activates GIRK (inwardly rectifying potassium) channels
Endocannabinoids vs phytocannabinoids
endocannabinoids are endogenous cannabinoids, AEA and 2AG
- involved in appetite, pain processing, stress & anxiety, and learning & memory
phytocannabinoids include 9deltaTHC and cannabidiol (CBD)
THC
Difference between THC and CBD
THC:
- effects include: euphoria, appetite stimulant, analgesic, anti-emetic, psychosis, memory effects, hallucination
- agonist of CB1 and CB2 receptor
CBD:
- does not cause a ‘high’, anti-epilepsy
- unclear how it works
How does THC work?
Binds to CB1 receptors on glutamatergic and GABAergic neurons disrupting normal endocannabinoid retrograde signalling from dopaminergic neurons.
- endocannabinoids fine-tune the activity of the mesolimbic dopamine projections through modulating both excit and inhib signalling (the endocans. are made in the post-synaptic neuron and diffuse back into both glutamatergic and GABAergic neurons nearby that are involved in VTA signalling)
- THC fucks this up ^
ENDOCANNABINOIDS regulate the balance of glutamate and GABA signalling - which kind of explains how it can have varying effects - are you inhibiting an inhibitor or an excitor?
tolerance and cannabis
- decreased response to same dose with repeated exposure
- more drug needed to achieve same effect
- caused by compensatory mechanisms that oppose the effects of the drug
- CB1Rs normally inhibits NT release but with high-affinity ligand present the CB1Rs are downregulated and internalized so there is less inhibition of Nt release (tolerance to drug but also to endocannabinoids)
How do we make endocannabinoids
- stress
- exercise
- hunger
- pain
- time of day dependent
Biphasic effects of cannabinoids
variable, individual genetic effects and also dosage dependent, or maybe the ratio of THC to CBD matters
- remember you’re inhibiting both GABAergic and glutaminergic neurons. Balance.
endocannabinoids are involved in:
- cognitive function, attention, motivation
- appetite
- learning and memory
- vomit reflex
- pain control
- emotion and fear
THC is involved in:
- cognitive impairment
- appetite stimulation
- memory impairment
- can cause nausea or help with it
- can cause you to be hyper sensitive or help with pain
cannabis use disorder and withdrawal symptoms
you CAN develop dependence leading to withdrawal symptoms in some people when they cease usage.
withdrawal symptoms: irritability, mood and sleep difficulties, decreased appetite, cravings, restlessness
why AREN’T endocannabinoids and THC equivalent
Endocannabinoids act at the right time and right place, are precise and tightly controlled, and responsive
THC is imprecise and has multiple effects at once and affects all the systems
Why are the effects of THC hard to predict?
Sometimes you get varying effects because the THC can mimic natural cannabinoid signals but can have the opposite effect with heavy use or a high dose (starts to oppose endocannabinoid system)
- dose-dependent and dependent on endocannabinoid levels
