10.2. Marijuana/cannabinoids: Neurobiology and cannabinoid signaling

Pharmacodynamic mechanism:

Cannabis/marijuana acts at cannabinoid receptors.

CB1 cannabinoid receptors are located on:

presynaptic terminals for retrograde signaling

The endogenous ligands for CB receptors (CB1 andCB2) are:

endocannabinoids

Endocannabinoids (endogenous cannabinoids):

high lipid solubility

Two endocannabinoids:

1) Anandamide

- partial agonist for CB1 receptors

2) 2-AG

- full agonist for CB1 & CB2

Endocannabinoids are

lipid neurotransmitters and retrograde messengers

Endocannabinoids Signaling: No vesicles

Too lipid soluble to be stored in vesicles.Synthesized on demand in the post-synaptic side of the synapse

Travel retrogradely to the

pre-synaptic terminal and bind to CB1 receptors

Inactivation:

Degradation by enzymes

Two known cannabinoid receptors: CB1 receptor, CB2 receptor

Both metabotropic, coupled to Gi proteins.

CB1 receptor expression

Mostly in brain and spinal cord

CB2 receptor expression

Mostly in immune system

CB1 receptor

- Important for rewarding effects and "high" from cannabis.

- The most abundant GPCR in mammalian brain.

What is the function of Gi protein from CB1?

It acts to reduce the activity of voltage-gated Ca++ channels, thus inhibiting calcium-mediated neurotransmitter release.

What role do endocannabinoids play in plasticity?

They are involved in both short-term plasticity and long-term plasticity (LTP/LTD), which are components of learning.

Endocannabinoids are the:

principal components of retrograde synaptic signaling.

low doses of THC in animals

conditioned place preference (CPP), self-administration

High doses of THC in animals

conditioned place aversion (CPA),no self-administration

What do CB1 agonists do to dopamine firing in the VTA?

CB1 agonists increase dopamine firing in the VTA.

How do CB1 agonists affect dopamine release in the NAc?

CB1 agonists increase dopamine release in the NAc via disinhibition.

What behavior do animals exhibit when given access to CB1 agonists?

Animals will self-administer CB1 agonists directly into the VTA or NAc.

Cannabinoid effects: Feeding

Cannabinoids injected i.v. or into NAc cause pleasurable reactions to tastes: "munchies"

Cannabinoid effects: Memory

- Cannabinoids into hippocampus cause deficits in working memory

- Blocked by CB antagonist rimonabant into hippocampus

Roles for endogenous cannabinoids

Conclusion: Endocannabinoids are normally involved in reward, feeding, and learning.

Endocannabinoid roles Reward: CB1 antagonists or CB1 gene knockout:

- Block self-administration of THC -- but also decrease self-administration of other drugs: alcohol, opioids, cocaine, nicotine.

- Decrease sensitivity to all rewards (food or drugs) and decrease NAc dopamine release.

Endocannabinoid roles: Feeding

- CB1 antagonist AM6545 decreased food consumption

- reduced motivation and reward.

What is the effect of CB1 knockout in mice on fear learning?

CB1 knockout mice show normal fear learning.

What is impaired in CB1 knockout mice during extinction learning?

CB1 knockout mice exhibit impaired extinction learning and continue to freeze.

What role do endocannabinoids play in extinction learning?

Endocannabinoids are important for extinction learning, likely due to their role in long-term depression (LTD) at synapses.

What effect do CB1 knockout mice have on memory retention?

CB1 knockout mice show enhanced retention of other types of memory.

How do CB1 knockout mice perform in recognition memory?

CB1 knockout mice retain recognition memory for longer.

THC effects in mice:

- Rewarding

- Increases feeding (pleasure)

- Impairs learning/memory

- Hypoalgesic (reduced pain)

- All blocked by CB1 antagonist.

CB1 antagonist or knockout effects:

- Reduces reward

- Decreases feeding (motivation)

- Impairs extinction learning

- Hyperalgesic (enhanced pain)

Indicates that THC mimics and amplifies the normal

role of endocannabinoids in reward, feeding, and memory

Adverse effects: Cannabis addiction

- Cannabis use can lead to addiction

- Treatment options mostly centered on psychosocial therapy

What are the long-lasting effects of repeated cannabis use that remain even after long abstinence/withdrawal periods?

Lung damage? Not really

Reduced cognitive function? Maybe

Increased risk for psychosis? Yes

Adverse effects: Lung damage?

No clear evidence of long-term lung problems with occasional or low marijuana use.

Adverse effects: Reduced cognitive function?

- Some impairments to decision making

- 3 weeks+ of abstinence

- reduced gray matter in areas of orbitofrontal cortex (even with similar IQ).

Adverse effects: Reduced cognitive function? (3)

- Reduced cognitive (memory) function

- Reduced dendritic complexity in prefrontal cortex

Conclusion: CB1 receptors are important in neurodevelopmental changes during adolescence

Adverse effects: Increased risk for psychosis? (1)

- Studies have found an increased incidence of psychosis among cannabis users

- daily use and high-potency cannabis

- Psychosis risk increases even more during early abstinence/withdrawal

- Cannabis-induced psychosis dramatically enhances the risk of transitioning to chronic psychosis

What does the comprehensive report on cannabis review?

Recent research on health effects of recreational and therapeutic use

What trend was observed regarding cannabis users in the U.S.?

The number of cannabis users aged over 12 increased

Therapeutic effects (conclusive evidence)

- reduced pain

- reduced nausea/vomiting

Risks (conclusive evidence)

- Increased risk of motor vehicle accidents

- Impaired learning, memory, and attention

What is the risk of cancer associated with repeated use?

No increased risk of cancer (but newer reports find otherwise)

What respiratory condition is associated with repeated use?

Chronic bronchitis

What mental health conditions have an increased risk due to repeated use?

Increased risk of developing schizophrenia and psychoses

What anxiety disorder is linked to repeated use?

Increased risk of social anxiety disorder

What is a concerning thought that can increase with repeated use?

Increased thoughts of suicide