DBM - Chapter 14 - Marijuana and Cannabinoids

tetrahydrocannabinol (THC)

main psychoactive compound

vaporizes and enters lungs in small particles

effective dose and latency to onset » influenced by amount and potency of platt, patterns of smoking

metabolism of THC

metabolized by CYP enzymes in liver: CYP2C9, CYP2C19, CYP3A4

>80 metabolites: 11-hydroxy THC, THC-COOH

• present for more than 2 weeks in urine after single uses

• basis of urine drug screens

11-hydroxy THC » psychoactive

THC absorption and elimination

easily absorbed by lungs » blood plasma levels rise quickly

declines rapidly after smoking » elimination half-life ~20-30 hours

• complete elimination much slower because of persistence in lipid depots (fat tissues)

PO THC

metabolized by the liver » ~50% because 11-OH-THC, much higher concentration than with inhalation

takes 30-90 minutes for initial psychoactive effect » “high” is longer-lasting, peak at 2-4 hours

CB1 receptor

widely expressed in body, not related to any known NT or peptide receptor

brain has more CB1 receptors than any other GPCR

low levels by many other organ systems: endocrine, immune, heart, liver

CB receptor method of action

signal via Gi: inhibit AC, inhibit VGCCs, open K+ channels

majority located on axon terminals (presynaptic)

• inhibit NT release

• THC: partial agonist at CB1 and CB2 receptors

CB receptors » powerful inhibitory effect on NT release

CB2 receptors

expressed by neurons in some areas of the brain » lower levels than CB1

found in immune system and other tissues: bone, fat, lung, testes, GI

also expressed by microglia and astrocytes

CB1 activation - behavioral effects

1. reduced locomotor activity

2. hypothermia

3. catalepsy

4. hypoalgesia (decreased pain sensitivity)

blocked by pre-treatment with CB1 antagonist

CB1 activation in hippocampus » spatial learning deficits in animals

• blocked by rimonabant

• cannabinoids inhibit LTP in hippocampal CA1

rimonabant

THC enhances incentive motivational properties of food

• CB1 receptor antagonists reduce food consumption

approved as anti-obesity medication 2006-2008 » removed after adverse psychiatric side effects

arachidonoyl ethanol amide (AEA or anandamide)

endocannabinoid » retrograde messenger (post → pre)

partial agonist at CB1

relatively little efficacy at CB2

2-arachidonoylglycerol (2-AG)

endocannabinoid » retrograde messenger (post → pre)

much higher quantities in the brain

full agonist at both CB1 and CB2

endocannabinoids

retrograde messengers, selective binding to CB1 receptors on pre-synaptic terminal

not packaged into vesicles » manufactured on demand

• synthesized from membrane inositol phospholipids that contain arachidonic acid

small lipid molecules » membrane permeable

endocannabinoid release

rise in intracellular Ca²⁺ » Ca²⁺ sensitive enzymes produce endocannabinoids

1. local depolarizing event opens VGCCs

2. rise in intracellular Ca²⁺ stores (via PLC activation)

3. Ca²⁺ influx via NMDA receptors

endocannabinoid metabolism

anandamide: fatty acid amine hydrolase (FAAH)

2-AG: monoacylglycerol lipase (MAGL)

reuptake: endocannabinoid membrane transporter?

depolarization-induced suppression of inhibition (DISI)

presynaptic inhibitory cell (GABA-ergic)

• post-synaptic depolarization » open VGCCs » elevation of intracellular Ca2+ » 2-AG production

• diffuses to presynaptic terminals of GABAergic interneuron that usually suppress firing

• leads to release of GABA inhibition » increased firing of postsynaptic cell

depolarization-induced suppression of excitation (DISE)

presynaptic excitatory cell (glutamatergic)

• in hippocampus, glutamate binds to mGlur5 receptors » activates PLC » 2-AG release

• 2-AG diffuses to nerve terminal, activates CB1 receptors, reduces glutamate release

endocannabinoids and pain

modulate pain perception and inflammation

rimonabant:

• hyperalgesia in WT mice (increased pain sensitivity)

• hyperalgesia in CB1 and CB2 KO mice

THC:

• hypoalgesia in WT mice (decreased pain sensitivity)

• cannabinoids equipotent to morphine

robust anti-inflammatory activity of topical THC » reduced mast cells, histamine release, myeloid immune cells

endocannabinoids and anxiety

overexpressio not MAGLin in hippocampus » enhanced 2-AG breakdown

leads to decrease in 2-AG concentration, but no change in AEA

increased anxiety-like behavior

endocannabinoids and fear learning

facilitate extinction of learned fear responses

• rimonabant inhibits extinction

increased endogenous anandamide » enhanced ability to “turn off” responses to threatening stimuli (habituation)

cannabidiol (CBD)

lacks psychoactive effects of THC (not schedule 1)

very low affinity for CB1 or CB2 receptors

may act as negative allosteric modulator of CB1 receptors

may function to inhibit breakdown of endogenous cannabinoids » enhanced activity

may lead to activation of 5-HT1A receptors » anxiolytic effects

may lead to allosteric enhancement of glycine receptor activity, inhibition of adenosine uptake » increased adenosine signaling

effects of marijuana

1. “buzz”

2. “high”

3. being “stoned”

4. “come-down”

“high” - associated with euphoria, exhilaration, disinhibition

“stoned” - usually reported relaxation

acute adverse effects of cannabinoids

high doses » increased anxiety

transient psychotic symptoms: depersonalization, derealization, agitation, paranoia and violent behavior

flashbacks

acute toxic reaction » CNS excitation or depression, tachycardia, gastrointestinal symptoms

physiological responses to cannabinoids

increased blood flow to the skin and flushing, increased heart rate, hunger

acts on CB1 receptors in blood vessels

• relaxation » vasodilation

• reduced with pretreatment with rimonabant

marijuana and cognitive function

most consistent acute effect » learning and memory (immediate recall, episodic memory)

heavier use » reduced adverse effects of acute cannabinoid exposure » theory of behavioral (“cognitive”) tolerance in heavy users

reinforcing properties of cannabinoids

do not have robust rewarding and reinforcing properties

• lever pressing for THC stops when saline substituted

• lever pressing for THC blocked by pretreatment with rimonabant

reinforcing effect dependent on CB1 receptor activation

mechanisms of cannabinoid reinforcememnt

activation of mesolimbic DA system

• CB1 receptor activation » stimulates firing of VTA neurons, enhanced DA release in NAcc

• inhibition of GABA release onto VTA neurons by presynaptic CB1 receptors

opioid agonists enhance self-admin, opposite with opioid antagonists

cannabis tolerance

regular usage » shown tolerance to:

1. acute intoxicating effects

2. impairment of cognitive function

3. feelings of anxiety

4. physiological changes, such as tachycardia

acute effects of cannabinoid exposure

impaired learning and memory

impaired working memory

impaired attention

impaired inhibitory control and executive functions

impaired psychomotor functions

chronic effects of cannabinoid exposure

impaired verbal learning and memory

impaired attention, attentional bias

possibly impaired psychomotor function

possibly impaired executive function

tolerance to THC and cannabinoids

largely pharmacodynamic » desensitization and down-regulation of CB1 receptors

desensitization as a result of internalization of receptors off cell membrane

animal studies with chronic THC

no withdrawal signs

long elimination half-life of THC

cannabinoid receptors remain partially activated

rimonabant - chronic THC

precipitated withdrawal - rimonabant blocks receptors even with THC present

decreased DA firing in the VTA and reduced DA release in the NAcc

increased CRF release in amygdala

increased secretion of stress hormones (corticosterone)

animals show abstinence symptoms

THC and reproductive functions

surpasses release of LH (luteinizing hormone)

in men, decreases testosterone level and sperm counts

animal work: pregnancy failure, retarded embryonic development, fetal death

designer cannabinoid “K2”

synthetic cannabinoid - experiences similar to those produced by marijuana: elevated mood, relaxation, altered perception

some reported psychotic effects: anxiety, paranoia, hallucinations

Schedule I