Exam 3: Cannabinoids Flashcards
for the cannabinoid system was the receptor iscovered first or the endogenous ligand for the receptor
receptor first in 1988 - recent
psychoactive cannabinoids exert their effects by interacting with the ____
endocannabinoid neurotransmitter system
what are the 2 natural endocannabinoids
anandamide
2-AG (2-arachidonylglycerol)
on-demand synthesis and release of cannabinoids requires
increased calcium ions in postsynaptic neuron!!!
endocannabinoids are generated from
inositol phospholipids in the membrane that have fatty acid arachidonic acid
what converts NAPE into anandamide
phospholipase D
what is the precursor to 2-AG
DAG
2-AG and anandamide are taken up by
endocannabinoid membrane transporters on glial cells
COX-2
breaks down both 2-AG and anandamide
FAAH
breaks down anandamide into arachidonic acid and ethanolamine
MAGL
breaks down 2-AG into arachidonic acid and glycerol
2 cannabinoid receptors
CB1 and CB2
general description of cannabinoid receptors
inhibitory
metabotropic
- inhibit cAMP formation, voltage sensitive Ca channels, and they open K channels
presynaptic heteroreceptors - retrograde signaling
CB1 receptors
located on axon terminals
presynaptic - typically on glutamate or GABA neurons
concentrated in brain and spinal cord!!
CB2 receptors
most abundant outside CNS (for in CNS it is hippocampus and cerebellum)
immune system, bone, fat, GI tract
expressed by microglia
what is a partial agonist at CB1 receptors ONLY
anandamide
what is a full agonist at CB1 and CB2 receptors
2-AG
3 endocannabinoid signaling mechanisms discovered
- retrograde signaling
- anandamide remains in postsynaptic cell and activates a canabinoid receptor or TRPV1 receptor
- endocannabinoids activate receptors on nearby astrocytes, resulting in release of glutamate
endocannabinoid always synthesized in…
POSTSYNAPTIC element!!!
inc in intracellular Ca in postsynaptic triggers it
endocannabinoid retrograde signaling
CB1 receptors are activated by 2-AG and inhibit Ca mediated neurotransmitter release
CB1 receptors found on synapses with MGlu5 receptors in hippocampus and cerebellum
negative feedback mechanism for regulating glutamate
- glutamate activates MGlu5 receptor
- this inc intracellular Ca and triggers 2-AG synthesis and release
- 2-AG diffuses across synapse and activates presynaptic CB1 receptors
- inhibits voltage gates Ca channels and reduces glutamate release
TRPV 1 receptors in brain
regulate pain processing, mood, motor function, learning and memory
- spicy foods
cannabis
marijuana and hemp produced from the cannabis plant
2 most abundant cannabinoids
THC and CBD
what is marijuana potency dependent on
THC content
it varies deending on growing conditions and the genetic strain of the plant
cannabis indica
female plant, 3-7 ft tall, less than 5% THC - growing towards 10%
stringer/smellier “skunk weed”
cannabis sativa
most common
grows up to 18ft tall
produces 1-5lb of buds/smokable leaves
low level of THC (less than 3%)
what differs between cannabis indica and sativa
indica is more potent has more THC
both have same pharmacodynamics
sinsemilla
without seeds
no pollination
highest level of THC (5-11%) very potent THC
resin (hashish) thc content
15-20%
hash oil THC content
exceeds 60%!! - moe potent than smoking a bud from the actual plant
what has happened to the potency of thc cannabis overtime
it has dramatically increased
what class is marijuana
schedule 1 drug
- recretional use legal in 18 states
medical use lgeal in 37 states
BUT federally it has no accepted medical use
ROA for marijuana
inhalation: smoking (joints, pipes, bongs)
- typical joint has 0.5-0.8g cannabis with 8% THC
- vaporization: inhalation, ingesting water vapor
oral: edibles - pills, brownies, gummies
topical: oils/creams marketed for local activity, high CBD, low THC
Dabbing: cannabis extracted with butane to form waxy residue with high THC
absorption of marijuana
smoking:
- THC easily absorbed by lungs
- 20-70% original THC in joint reaches lungs (only 30% enters circulation)
oral administration: GI tract, delayed onset of action, dec bioavailability
- first pass metabolism - low and variable blood concentrations
- 50% THC metabolized to 11-OH-THC before entering circulation
distribution of marijuana
high lipid solubility - cannabinoids persist in body for long time - weeks to months if chronic user (crosses BBB and placental)
THC carried by blood and deposited in organs
Depot binding!!! - accumulates in fat stores over long period of time it is released into circulation - can detect on drug test for a while
smoked/vaped: rapid onset of action
oral: delayed onset but lasts longer
metabolism of marijuana
oral: first pass metabolism
- 50% THC metabolized to 11-OH-THC
excretion of marijuana
55% excreted as feces!!!
20% in urine
blood THC levels decline quick but complete elimination is much slower due to fat tissue
psychoactive annabinoids exert their effects by interaction with the ____
endocannabinoid neurotransmitter system
where are CB1 and CB2 receptors found?
CB1: cns, lungs, liver, kidneys
- presynaptic heteroreceptors regulate releas of other neurotransmitters
CB2: immune system, GI tract
mechanisms of reinforcement
- activation of mesolimbic DA system
- cannabinoids INDIRECTLY stimulate firing of DA neurons in VTA an enhance DA release in nucleus accumbens
are CB1 receptors expressed by DA neurons?
NO
- cannabinoids activate CB1 receptors in GABAergic neurons of VTA reducing local GABA release
which releases DA neurons from inhibitory effects of GABA increasing cell firing
THC effect on user: amygdala
panic/paranoia
THC effect on user: basal ganglia
slower reaction time
THC effect on user: brain stem
antinausea effects (medulla) and suppressed pain
THC effect on user: cerebellum
impaired coordination
THC effect on user: hippocampus
impaired memory, forgetful
THC effect on user: neocortex
altered thinking, judgement, sensation, PFC changes
THC effect on user: nucleus accumbens
euphoria - indirectly activate DA
THC effect on user: spinal cord
altered pain sensitivity
THC: learning and memory
cannabinoids suppress induction of long term potentiation (needed for learning) in the hippocampus by inhibiting glutamate neurons
long term potentiation aka learning requires glutamate!!
- spect imaging shows reduced blood flow to hippocampus
THC: pain
CB receptors in the PAG in brainstem on cells that process pain signals - lots of CB1 in PAG, lots of CB2 in spinal cord
activating CB1 will shut down the PAG and block pain signals from getting to brain
CB1 and CB2 receptors regulate both pain perception and the cognitive-affective responses to pain
what receptors does CBD oil target vs THC
CBD oil targets CB2R
THC targets both CB1 and CB2
effects of cannabinoid use depend on
dose
frequency of use
characteristics of user - male or female
setting
what is the “high” associated with
euphoria, exhiliration, sense of disinhibition
relaxation is the most common reported effect of being___
stoned
sensroy rxns: floating sensations, enhances visual and auditory perception, visual illusions, slowing of time
how much to smoke and eat to get mild euphoria
2mg smoked
5mg eaten
how much to smoke or eat to get perceptual and time distortions
7mg smoked
17mg eaten
how much to smoke or eat to get hallucinations, delusions, disortions of body image
15mg smokes
25mg eaten
is there a lethal dose?
NO
LD50 ~ 1:40,000
nearly 1,500 lbs of marijuana in about 15 min to kill onself - you wuld die of smkoe inhalation first
acute effects
inc flushing of skin, blood flow o skin, inc HR, vasodilator (blood shot eyes), pupils dilate
inc hunger
reduced motor activity/drowsiness
what brain regions involved in THC effects on hunger/feeding behavior
VTA and Nucleus Accumbens: enhanced pleasure from eating (why does this taste so good)
Limbic system: enhanced palatability (getting creative in kitchen)
Stomach and SI: regulates ghrelin, appetite stimulating hormone
Hypothalamus: inc craving/food intake
effects of cannabinoids on psychomotor performance
acute exposure produces deficits in driving ability
- slow rxn time, poor coordination, drowsiness
bigger effects when marijuana combined with alcohol or other drugs
smoking marijuana can sometimes produce transient psychotic symptoms
agitation, paranoia
- expectation also plays role in what effects the drug will produce
acute effects cannabinoid
impaired verbal learning and memory impaired working memory impaired attention impaired inhibitory control and other executive functions impaired psychomotor function
chronic effects cannabinoids
impaired verbal learning and memory
impaired attention; attentional bias
possibly impaired psychomotor function
possibly impaired executive function
recovery of function with abstinence
likely persistent effects on attention and psychomotor function
possibly persistent effects on verbal learning and memory
amotivational syndrome
chronic cannabis use associated with aimlessness, dec motivation, lack of planning, dc productivity
cannabis and educational performance
inverse relationship
inc cannabis dec educational performance
poor academic performance can also inc canabis use
tolerance
regular users report tolerance to behavioral and subjective effects
memory impairment, motor coordination, accelerated time passage
PET imaging shows
widespread decreases in brain CB1 receptor binding in regular marijuana smokers
- receptor binding recovered following abstinence from cannabis within a few days
chronic cannabis exposure could change brain
unclear if brain abnormalities occurred prior to or after marijuana use
impaired striatal dopamine function: long term disturbances in mood, motivation, cognition
physical health
smoking marijuana damages lungs
- smoke contains tar, carcinogens, carbon monoxide
regular marijuana smoking is associated with various respiratory symptoms
risk of heart attack significantly elevated during the hour after smoking marijuana, even ppl in 20s or 30s
reproductive consequences
males and females
males: developing breast tissue due to inc release of breast-feeding hormone prolactin
- reduced sperm production and motility, erectile dysfunction
females: menstrual cycle irregularities
if used during pregnancy crosses placenta to fetus
- adverse effects may persist through adulthood
medical uses of cannabis: cancer
reduces nausea and vomiting associated with chemo
limited evidence showing reduced tumor growth in patients
medical uses of cannabis: weight
promotes weight gain in disorders that diminish appetite
medical uses of cannabis: pain
reduces neuropathic pain from trauma or surgery
medical uses of cannabis: glaucoma
relieves intraocular eye pressure
medical uses of cannabis: autoimmune disease
inhibits immune system functioning
appears effective for multiple sclerosis
