cannabis and plant derived cannabinoids Flashcards
What are the active constituents in cannabis
Psychoactive component: 9-tetrahydrocannabinol
(9-THC) - identified in 1964
non psychoactive component: Cannabidiol (CBD) – identified in 1934
Cannabis sativa: THC > CBD
Cannabis indica: CBD > THC
CBD does not activate cannabinoid receptors
dif types of cannabis have different amounts- sativa gets you high
What are the different types of cannabinoids
Plant-derived cannabinoids (or phytocannabinoids) – naturally occurring, found in plants
Synthetic cannabinoids – not found in nature
Endogenous cannabinoids – naturally occurring, produced by our body
Describe cannabis
Large number of active compounds
A range of pharmacological targets
The precise pharmacological profile depends on the active compound in question
Describe CB1 and CB2 receptors
both G protein coupled
Gi/o inhibit adenyl cyclase, decreasing cAMP levels in cells
encoded by 2 separate genes
n termius usually ligand binding, binding membrane within transmembrane domain
the size, shape of N terminus will affect how well the ligand can bind and determines what acts as an agonist or antagonist etc
CB1 is the subtype present in the brain, mainly binds THC (partial agonist)
CBD doens’t bind to CB1 receptors in the brai so it’s not psychoactive
Radio ligand signalling
radio ligand binding- tells you about the binding of a ligand to its receptor
says nothing about efficacy 41
tells you if it binds- not efficacy or agonist or antagonist
ligand is radiolabelled
increase concentration of cannabinoid
measure radioactivity
CB1 receptor signalling
Gi and Go
Signalling downstream of CB1 activation
Inhibition of adenylyl cyclase
Inhibition of voltage-gated Ca2+ channels
Activation of inwardly rectifying K+ channels
Activation of MAP kinases
Longer-term changes: gene expression etc
this makes neurones less excitable
long term changes are changes in MAP kinases
Describe presynaptic CB1 receptors
neurones have high concentration of CB1 receptors, particularly those in the brain
cb2 receptors primarily in immune cells eg macrophages, lymphocytes- some in brain and some in periphery
most cb1 receptors are pre synaptic
action potential acticates calcium influx through VGCC activating fusion with pre synaptic membrane, releasing neurotransmitters into pre synaptic cleft
when you activate CB1 receptors, increased potassium efflux, makes membrane potential less positive, reducing ability of vgccs to open, reduces neurotransmitters released
CB1 receptors in the CNS:
most cb1 receptors are in the green areas
highest density areas are cortical region, hippocampus, striatum, cerebellum
Describe how CB1 affects the reward pathway
in vivo
measuring glutamate being released from pre-synaptic terminal
spike is because of depolarising membrane potential
right: result of implanting electrodes in rat and effect on PFC
measuring activity in conscious rat
control is baselines activity of glutaminergic transmission
win and win inhibits spike activity
suggests agonist reduce glutaminergic release
but if you block cb1 receptors, you block the effect of these agonists
CB1 – often found in GABAergic interneurons
Reduced inhibitory input increase firing rate of dopaminergic neurons in VTA and nucleus accumbens?
similar thing happens in GABAnergic neurones
common in interneurones- lot of interneurones in cortex
Describe CB1 and neurotransmission
Involve a range of neurotransmitters: glutamate, GABA, dopamine, acetylcholine, noradrenaline, CGRP
Evidence from brain slices and animals/tissues with intact innervation
Modulate functions in the brain, cardiovascular and respiratory system, gut motility etc
What are the effects of cannabis/THC on CB2
THC is also a partial agonist at CB2
Anti-inflammatory
Immunosuppressive
Analgesic
Peripheral vs central CB2
Atherosclerosis
Microglia; neuroinflammation; neurodegeneration
CB2: Primarily in immune cells (e.g. macrophages & lymphocytes)
Alternative targets of cannabis
Alternative targets
doesn’t just bind to cb1 and cb2
while thc can activate these
these are not the only pharmacological targets in cannabis
think about anti-inflamatory, anti-cancer and anti-anxiolytic effects
eg 5HT1A activated has been linked to anxiolytic properties
so if CBD activates same channel it’sprobably also anxiolytic
one component is an antagonist of cb1 and agonist of cb2 interstingly
CB1/CB2 receptors
5-HT1A receptors
Transient Receptor Potential Vanilloid receptor (TRPV1)
Ca2+ channels
Peroxisome proliferator-activated receptor (PPAR)
Enzymes for endocannabinoid degradation (FAAH)
What are some agonists for synthetic CB receptor agonists?
THC: partial agonist for CB1 and CB2 CP55940 HU210 WIN55212-2 JWH133 JWH018 AM2201
These are 100 times more potent than THC
massive issue high concentrations- eg in prisons due to paranoia and other side effects
What are some synthetic analogues of THC
Nabilone (Casamet)
Marketed since 1983
suppression of nausea and vomiting during chemotherapy
(and anorexia in AIDS patients)
not first line of treatment
can be useful if patient resistant to other anti-nausea, anti-emetic medication
What is Sativex
used for pain control in MS
may help w motor control in long term
spray underneath tongue
doesn’t really give people high effect as THC is quite low
cannabidiol CBD uses
Epilepsy?
Cannabis oil on prescription?
Cannabidiol oil?
Epidiolex (cannabidiol) for seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in USA
used for certain types of epilepsy- used for specific chilhdood epilspey
reduced number of seizures
suggest CBD useful for ocntrolling siezures
