Chapter 14: Marijuana And The Cannabinoids Flashcards
The psychoactive properties of marijuana result primarily from two phytocannabinoids
THC
Cannabidiol (CBD)
THC
- inhaled or oral
- 20-30% absorbed into lungs
- lower bioavailability with oral consumption
- partial agonist at CB1 receptor
Cannabidiol
- bioactive
- low affinity- many possible targets
- therapeutic
[…] and […] can be added to cannabinoids
Terpenes and flavanoids can be added to cannabinoids
Sinsemilla
Produced without seeds
Hashish
Cannabis extract that can be smoked
THC is metabolized by the […] and distributed in […]
THC is metabolized by the liver and distributed in adipose
THC metabolites
11-OH-THC: metabolization occurs rapidly
- shows recent use
THC-COOH: carboxylation
- half-life- 1 week
- gets redistributed to other tissues, specifically adipose tissue
THC Excretion
2/3 in feces
1/3 in urine
11-OH-THC Half-life
20-30 hours
THC Oral consumption
First pass metabolism reduces bioavailability
Administration of THC effects
- Reduced locomotor activity
- Hypothermia
- Catalepsy as indicated by immobility in ring test
- Hypoalgesia (reduced pain sensitivity)
2 different cannabinoid receptors
CB1
CB2
CB1 receptors
- primary CB receptor in the CNS
- wide distribution: cortex, basal ganglia, hippocampus, cerebellum
- presynaptic nerve terminal
- Gi/o, increased gk, and decreased gca
CB2
- peripheral (bone, fat, GI)
- microglia
- low expression in neurons
- CB2 agonist- mediated cytokines suppression
Endocannabinoids are […] derivative of membrane phospholipid
Endocannabinoids are fatty acid derivatives of membrane phospholipid
Anandamide
2-AG
Anadamide
Arachidonoyl ethanolamine (AEA)
- CB1 partial agonist
- multiple synthetic pathways
- degraded by FAAH (fatty acid aside hydrolase)
- very, very nonpolar
2-AG
2-arachidonoylglycerol
- full agonist, non selective
- CB1 and CB2
- degraded by MAGL (monoacyl- glycerol lipase)
- COX-2: enzyme that plays important role inflammation
- COX-2 inhibitors: nonsteroidal anti-inflammatory drugs (NSAIDs)
DAG lipase (DGL) converts […]
DAG lipase (DGL) converts DAG —> 2-AG
- increased [Ca2+] by VGCC or NMDA-R
- GPCR/ PLC (also PLA2 and PLD)
Monoacyl- glycerol lipase (MAGL)
Degrades 2-AG
Uptake transporter
Characterization is incomplete
There are 3 different signaling mechanisms used by endocannbinoids
Retrograde signaling- usual mode of altering communication
Non-retrograde signaling
- TRPV1- nonspecific cation channels (capsaicin receptor)
Neuron- Astrocytes signaling
Retrograde signaling by endocannabinoids is involved in synaptic plasticity
Homosynaptic excitatory LTD: released Glu
Heterosynaptic inhibitory LTD: released GABA
Pharamcological and genetic techniques are used to determine the roles of CB receptors
Ligands
Knock-out mice:
- CB1, CB2, FAAH, or MAGL KO
Pharmacological technique ligands
CP-55940 and WIN 55212-2: full agonists CB1 and CB2
SR 141716A (rinomabant): selective CB1 antagonist
CB1 receptors involved in brain’s reward system:
- Reductions in rewarding effects of natural substances such as food/ sweetened solutions in animals that lack eCB activity
- Enhanced reward due to pharmacological manipulation that increase eCB signaling
CB1 receptors mediate many of the effects of TNC and endocannabinoids
Resultant effects of THC in mice
- decreased locomotion
- hypothermia
- catalepsy
- hypoalgesia
Functional effects of cannabinoids
- decreased nausea/ vomiting
- memory/ extinction (impairs episodic, verbal memory and working memory)
- anxiolytic, antidepressant
- analgesic
- decreased seizure
4 stages in infrequent THC use
- Buzz
- High
- Stoned
- Come-down
Reinforcement
Activation of DA neurons in VTA and increased DA release to N Acc
- cannabinoids activate CB1 receptors in GABAergic interneurons of VTA —> reduction in local GABA —> cell firing
eCB signaling is anxiolytic and antidepressant
In humans, acute cannabis produces feelings of relaxation, reduced anxiety and elevated mood
- converging lines of evidence in rodents illustrate the anxiolytic and antidepressant effects of eCB signaling
eCB signaling is anxiolytic and antidepressant: increase eCB
- eCBs are anxiolytic in EPM, light-dark test
- inhibition of FAAH prevents anxiety-like behaviors following social defeat stress
eCB signaling is anxiolytic and antidepressant: decrease eCB
- CB1 KO show increased anxiety
- mice with disrupted DGLa increases both anxiety and depression
DGLa deletion
- reduces 2-AG in PFC, amygdala, and striatum
- increases anxiety
- increased anhedonia
There is limited evidence that cannabinoids improve symptoms of depression
No RCTs have specifically evaluated cannabis in patients with a depressive disorder
- evidence is inconclusive
There is limited evidence that cannabinoids improve symptoms of anxiety
- only 1 RCT with high risk of bias (small N) found greater improvement with CBD on a stimulated public speaking test
- 4 other RCTs examined anxiety symptoms in patients with chronic pain- 3 judged to have high risk of bias
Hyperalgesia is induced by:
CB1R or CB2R KO or chronic CB1R antagonist SR141716A
Analgesic mechanisms
- inhibition of transmitter and peptide release
- modulation of postsynaptic neuron excitability
- activation of descending inhibitory pain pathway
- reduction of neural inflammation
Cannabinoids affect the cognitive aspects of pain
mGluR5 in mPFC
- PLC—>DAG—>DAGLa—> 2-AG synthesis
2-AG activated presynaptic CB1
- decreased GABA release, mPFC in disinhibited - driving inhibitory neurons in the amygdala
There is substantial evidence that cannabis is an effective treatment for chronic pain in adults
RCTs that compared cannabinoids to usual care, a placebo, or no treatment for 10 pain conditions
- OR of reporting 30% or greater reduction of pain
The first FDA- approved drug that contains a purified drug substance derived from marijuana
Epidiolex
- Lennox-Gastaut syndrome
- Dravet syndrome
The addiction potential of THC
- humans and squirrel monkeys self-administer THC
- rodents and Theseus monkeys do NOT
THC self-administration: role of CB1
- blocked by SR141716A
- 2-AG is also self-administered
Cannabinoids are atypical drugs of abuse
Self- administration
- only under certain conditions - eg. Pre-exposed to drug, food, or H2O deprived, etc
Conditioned place preference
Threshold of ICSS
- CBS are reinforcing under the appropriate experimental conditions and choice of species
Amotivational Syndrome
State of relaxed and careless drifting after significant marijuana use
Cannabinoids act on CB1 receptors on GABAergic interneurons in the VTA to inhibit GABA release
CB1-R in VTA
- hyperpolarize IN
- decrease GABA release
- increase VTA firing
- increase DA release
CB1 and MOP receptors seem to work together
MOR in VTA
- increased DA release
- CBS lose rewarding properties in MOR-KO
Chronic CB administration leads to tolerance and precedes precipitated withdrawal: Tolerance
- CB1 desensitization
- CB1 down-regulation
Chronic CB administration leads to tolerance and precedes precipitated withdrawal: Withdrawal
- Precipitated with SR 141716A
- decreased DA neuron firing
- increased CRF release in CeA
- increased stress hormones (ex. Corticosterone)
Precipitated Withdrawal
Administration of antagonist would abruptly block receptors despite continued presence of THC
