3. Marijuana Flashcards
Marijuana History/bkgd
made from cannabis sativa, marijuana tax act 1937 banned it
Schedule 1 drug THC, no medical use
basic pharmacology marijuana
contains over 120 phytocannabinoids
THC - main psychoactive compound, found in resin of female plants, THC content varies (inc. over yrs gene editing)
CBD - not psychoactive, conc. stable
THC metab/what is it/edibles
vaporizes and enter lung
latency/potency deals with pattern of smoking
metab’d in liver by CYP2C9,CYP2C19,CYP3A4 into 11-hydroxy THC and THC-COOH (present 2 weeks urine)
11-hydroxy-THC is psychoactive
THC easily absorbed to blood, elimination 20 hrs bc depot binding
edible THC metab’d into 11-OH-THC high conc. and can pass BBB easily, 30-90 min fora loong lasting high
CB receptor action
metabotropic Gi (inhibit AC, inhibit VGCC, open K channels)
few CB1 in respiratory/brain stem (less overdose deaths)
Located on axon terminals of presyn
Inhibit release of NTs
THC is a partial agonist of CB1/2
CB1 receptor
wide expression in body
not related to known NTs
brain has more CB1 than any other GPCR
CB2 receptor
expressed in neurons/lower conc than CB1
found in immune system and microglia/astrocytes
Behavioral tetrad of CB1 receptor
reduced locomotor
hypothermia
catalepsy
hypoalgesia
blocked if given CB1 antagonist
spatial learning deficit in hippocampus, cannabinoids inhibit LTP (effects blocked with CB1 antagonist rimonabant)
THC and food
THC enhances motivation of food
CB1 antagonists reduce eating
Rimonabant was an anti-obesity drug
endocannabinoids
human like substance that acitvates CB1/2 (why else would we have receptor)
AEA/anandamide - partial agonist of CB1, not of CB2
2-AG - found a lot on brain, full agonist of CB1/2
Both retrograde messengers (postsyn enzyme activates presyn receptors)
Endocannabinoid mechanism of action
retrograde messenger bind to CB1 on presyn
Not in vesicles, made on demand bc lipid soluble
Postsyn Ca2+ rise causes enzymes to make them (VGCCs open, rise in intracellular Ca, Ca influx NMDA)
Reuptake of endocannabinoids
FAAH - reuptakes Anandamide
MAGL - reuptakes 2-AG
Depolarization induced suppression of inhibition
retrograde signalling causes short-term synaptic plasticity
When inhibitory presyn (GABA)
Post-syn depol causes Ca, 2-AG production that diffuse to GABA presyn terminal and suppress firing/release
In hippo- endocannabinoids made by pyramidal cells
meaning an increase in post-syn firing in pyramidal cells
Depolarization induced suppression of excitation
when presyn cell is excitatory (glutamatergic)
in hippo, glutamate binds to post syn mGluR5, actiavtes PLC = 2-AG release diffuses to CB1 on presyn
Reduces Glutamate rleease
less excitation postsyn
endocannabinoids pain modulation
rimonabant (CB antagonist) causes hyperalgesia, more pain. CB1/2 KO have hyperalgesia too
THC causes hypoalgesia, less pain. CB1 agonist causes hypoalgesia, equipotent to morphine!
Topical THC is anti-inflammatory (less histamin/mast cell)
No pain case study had no FAAH enzymes = no breakdown of anandamine, hypoalgesia)
Endocannabinoids and anxiety
Overexpression of MAGL (breaks down 2-AG) causes anxiety
Endocannabinoids and fear learning
endocannabinoids do extinction of learned fear responses (when no more shock with bell, extinct the scared beh’r)
Rimonabant inhibits extinction
CB1 receptor enhancing drug for PTSD?!
Mutation of FAAH gene = more anandamide = habituate to scary faces quicker. inc. anadamide turns off response to scary stimuli (anandamide is an anxiolytic)
CBD what is/mech actions
no psychoactive effect, not schedule 1! (legal)
Low affinity of CB1/2 receptors
May act as negative allosteric modulator of CB1 receptors
May - inhibition breakdown of endocannabinoids, actiavte 5-HT1A receptors (anxiolytic), enhance allosteric glycine receptor inhibiting adenosine reuptake (more adenosine = sleepy)
Epidiolex and Histiocytoma
epilepsy drug for Lennox-Gastaut, Dravet using CBD
mechanism unknown
Topical CBD oil reduced tumor
subjective effects of cannabis
buzz/high/calm
high dose anxiety/psychoticism/tachycardia
Physiological and cognitive responses to cannabis
increased BPM/BP, increased hunger
THC acts on CB1 in blood vessles = vasodilation realxation, effect reduced with rimonabant
cog - learning/memory impaired, tolerance cand evelop where people dont experience adverse cog effects
Cannabis reinforcement, and opioid effect
no robust rewarding aspect
blocked with rimonabant
reinforcement depends on CB1 agonist activation, CPP and ICSS threshold reduction
acts on mesolimbic
CB1 stmiulates VTA/DA release in NAcc (because of GABA inhibition)
Opioids enhance self admin cannabis
opioid antags reduce self admin
abuse and tolerance of cannabis
5-10% capture ratio (due to stress/anxiety disorders)
tolerance develops to intoxicating effect/cog impairments/anxiety/physical changes like tachycardia
What kind of tolerance with THC
Pharmacodynamic - desensitization and down-regulation of CB1 receptors
lowered CB1 receptor density/binding
Chronic THC exposure
no withdrawl! long half life, CB receptors remain partially acitvated
Rimonabant - precipiated withdrawl (blocks receptors even with THC) = decreased VTA/DA release in NAcc, increase CRF amygdala, increase stress hormone
Animals show absitnence syndromes
No treatment for use disorder
maybe treat with CB agonist (like nicotine replacement)
