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Chapter 14: Marijuana and Cannabinoids - Coggle Diagram
Chapter 14: Marijuana and Cannabinoids
Marijuana Background
produced from flowering hemp (Cannabis sativa)
Schedule I Drug: no currently accepted medical use and high abuse potential, the most dangerous drugs of all drug schedules with potentially severe psychological/physical dependence
Basic Pharmacology
C. Sativa contains >100 unique cannabinoids
THC: Main psychoactive compound
concentrated in the sticky resin --> secreted by flowering tops of female plants
THC content and potency varies widey
Hashish has high THC content (10-15%)
THC vaporizes and enters lungs in small particles
effective dose and latency to onset: influenced by amount and potency of the plant used and patterns of smoking (hold duration, puff volume, puff frequency)
Metabolized by CYP enzymes in the liver
Metabolites (>80)
11-hydroxy THC
psychoactive
enters brain/passes BBB easier than THC itself
THC-COOH
present for more than 2 weeks in urine after single use, basis for drug screens
THC is easily absorbed by the lungs --> blood plasma levels rise quickly
blood THC levels decline RAPIDLY after smoking
BUT biological half-life is 20-30 hours
complete elimination from the body is slower because of persistence in fat tissues (lipid depots)
EDIBLES
oral THC bioavailability is only 6-10% (inhalation is 35%)
eaten cannabis gets metabolized by the liver --> delta9 THC becomes 11-hydroxy THC (passes BBB more rapidly)
much higher concentration of 11-OH THC after ingestion than inhalation
smoked/vaped cannabis doesn't create same levels of 11-hydroxy-THC that edibles do :
Mechanisms of Action
Cannabinoid Receptors
CB1 receptor: widely expressed in body
brain has more CB1 receptors than any other GPCR
CB1 receptor activation
behavioral tetrad
reduced locomotor activity
hypothermia
catalepsy: seizure, loss of sensation and consciousness
hypoalgesia: reduced sensitivity to pain
CB1 receptor activation in hippocampus --> spatial learning deficits in animals
CB1 agonist in hippocampus --> memory deficits in radial arm maze
effects blocked by rimonabant
not related to any known receptor for NTs or peptides in the brain
CB2: found in the immune system and other tissues (bone, adipose cells, GI tract)
CB receptors: metabotropic
signal via Gi
inhibit AC
inhibit V-gated Ca++ channels
open K+ channels
located on axon terminals (on presynaptic cell)
inhibit release of NTs
THC: partial agonist at CB1 and CB2 receptors
rimonabant: CB1 antagonist, obesity drug
can't overdose because CB1 receptors are lacking in brainstem regions that affect breathing/heart rate
Neurobiological basis for the munchies
endocannabinoids (and THC) enhance incentive motivational properties of food and food-mediated reward
CB1 receptor antagonists reduce food consumption
rimonabant: anti-obesity medication, removed from market after adverse psychiatric side-effects (because there are so many CB1 receptors in the brain)
Endocannabinoids
2 endocannabinoids: bind and activate CB1 receptors
AEA or anadamide
2-AG
found in much higher quantities in brain
main endocannabinoid for CB1 and CB2 receptors
retrograde messengers: postsynaptic to presynaptic
endocannabinoids bind selectively to CB1 receptors on PRESYNAPTIC terminal
NOT packaged into vesicles
manufactured on demand
small lipid molecules (membrane permeable)
Rise in intracellular Ca++ leads to release --> Ca++ sensitive-enzymes produce them
local depolarizing event causes VGCCs to open and Ca++ to enter
rise in intracellular Ca++ stores (via PLC activation)
Ca++ influx via NMDA receptors
signaling mechanisms
Retrograde signaling: Postsynaptic --> Presynaptic
Non-retrograde signaling: endocannabinoid remains within spine to activate either postsynaptic CB1 receptors or TRPV1 cation channels
Neuron-astrocyte signaling: endocannabinoids activate CB1 receptors on astrocytes --> provoke glutamate release from cells
Cannabinoid transporter?
Metabolic enzymes
Anandamide: FAAH in postsynaptic neuron
2-AG: MAGL in presynaptic neuron
MAGL KO mice: significantly icreased 2-AG concentrations
develop desensitization of CB1 receptors in CNS
Depolarization-induced suppression of inhibition (DISI)
Hippocampal pyramidal cells (GABA interneurons project to pyramidal neurons)
membrane depolarization opens v-gated Ca++ channels --> elevation of intracellular Ca++ concentrations --> 2-AG production
2-AG diffuses to terminals of GABAergic interneurons that would normally suppress firing of pyramidal cell --> increased firing of pyramidal cell
Depolarization-induced suppression of excitation (DISE)
In hippocampus, glutamate binds to postsynaptic mGlur5 receptors
activates PLC --> 2-AG release
2-AG diffuses to nerve terminal and activates CB1 receptors to reduce glutamate release (protective mechanism)
Endocannabinoids modulate pain perception and inflammation
WT mice given rimonabant exhibit hyperalgesia (increased pain sensitivity)
CB1 and CB2 KO mice also exhibit hyperalgesia
THC given to WT mice leads to hypoalgesia
WT mice given CB1 agonists do too
cannabinoids are equipotent with morphine
robust anti-inflammatory activity of topical THC
reduced recruitment of mast cells, decreased blood concentration of histamine, decreases in myeloid immune cell infiltration
Endocannabinoids and fear learning
endocannabinoids facilitate extinction of learned fear responses
rimonabant inhibits extinction
CB1 receptor enhancing drugs for PTSD
In humans, a SNP in FAAH gene --> increased endogenous anandamide levels
people with one copy of hypofunctioning alele habituated much quicker to images of threatening faces
increased anandamide levels enhance ability to turn off responses to threatening stimuli
CBD: one of 100 cannabinoid chemicals in marijuana plant
LACKS psychoactive effects of THC: no longer schedule 1
very low affinity for CB1/CB2 receptors
effective as anticonvulsant, antianxiety, analgesic, antitumor, antipsychotic
Epidiolex: to treat epilepsy
Acute Behavioral and Physiological effects
Subjective and behavioral effects of marijuana: 4 stages
"buzz" --> "high" --> being "stoned" --> the "come down"
Physiological responses
increased blood flow to skin and flushing, increased heart rate, increased hunger
THC acts on CB1 receptors in blood vessels
relaxation --> vasodilation
effects are reduced by pretreatment with rimonabant
Reinforcing properties of cannabinoids
Lever pressing by monkeys for THC stops when saline is substituted
lever pressing for THC is completely blocked by pretreatment with rimonabant
reinforcing effect depends on CB1 receptor activation
Mechanisms for reinforcement
activation of mesolimbic DA system
stimulate firing of VTA neurons in VTA and enhance DA release in NAcc
opioid agonists enhance cannabinoid self admin
Cannabis Abuse and Chronic Exposure
Tolerance
animals exposed to THC or other CB1 agonists develop tolerance to behavioral and physiological effects
combo of desensitization and down regulation of CB1 receptors
not relevant to human consumption
Withdrawal
no withdrawal signs because of long elimination half life of THC
CB receptors remain partially activated
Rimonabant
precipitated withdrawal: rimonabant blocks receptors even with THC present
decreased DA firing in VTA and reduced DA release in NAcc
increased CRF release in amygdala
animals show abstinence symptoms
used very high doses
withdrawal in humans: irritability, increased anxiety, depressed mood, sleep disturbances, heightened aggressiveness, decreased apetite
similar to nicotine withdrawal
symptoms can be relieved by smoking marijuana or oral THC
CB1 receptor activation and brain development
chronic treatment reduced PFC dendritic length and impaired LTP at hippocampal-PFC synapses
Adverse health effects: no deaths from overdose
smoking damages lungs - smoke contains tar, carcinogens, carbon monoxide
Chronic low dose THC --> reverse age-related cognitive decline
enhanced expression of synaptic proteins and increased spine density in hippocampus
THC and reproductive functions
suppresses release of luteinizing hormone
in men: decreases testosterone, sperm counts
animal work: pregnancy failure, retarded embryo, fetal death but NOT REPORTED in humans
in humans: positive association of marijuana use and sexual activity