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Neuropharmacology > Chapter 14: Marijuana And The Cannabinoids > Flashcards

Chapter 14: Marijuana And The Cannabinoids Flashcards

1
Q

The psychoactive properties of marijuana result primarily from two phytocannabinoids

A

THC

Cannabidiol (CBD)

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2
Q

THC

A
  • inhaled or oral
  • 20-30% absorbed into lungs
  • lower bioavailability with oral consumption
  • partial agonist at CB1 receptor
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3
Q

Cannabidiol

A
  • bioactive
  • low affinity- many possible targets
  • therapeutic
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4
Q

[…] and […] can be added to cannabinoids

A

Terpenes and flavanoids can be added to cannabinoids

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5
Q

Sinsemilla

A

Produced without seeds

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6
Q

Hashish

A

Cannabis extract that can be smoked

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7
Q

THC is metabolized by the […] and distributed in […]

A

THC is metabolized by the liver and distributed in adipose

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8
Q

THC metabolites

A

11-OH-THC: metabolization occurs rapidly
- shows recent use

THC-COOH: carboxylation

     - half-life- 1 week
     - gets redistributed to other tissues, specifically adipose tissue
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9
Q

THC Excretion

A

2/3 in feces

1/3 in urine

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10
Q

11-OH-THC Half-life

A

20-30 hours

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11
Q

THC Oral consumption

A

First pass metabolism reduces bioavailability

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12
Q

Administration of THC effects

A
  1. Reduced locomotor activity
  2. Hypothermia
  3. Catalepsy as indicated by immobility in ring test
  4. Hypoalgesia (reduced pain sensitivity)
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13
Q

2 different cannabinoid receptors

A

CB1

CB2

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14
Q

CB1 receptors

A
  • primary CB receptor in the CNS
  • wide distribution: cortex, basal ganglia, hippocampus, cerebellum
  • presynaptic nerve terminal
    - Gi/o, increased gk, and decreased gca
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15
Q

CB2

A
  • peripheral (bone, fat, GI)
  • microglia
  • low expression in neurons
  • CB2 agonist- mediated cytokines suppression
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16
Q

Endocannabinoids are […] derivative of membrane phospholipid

A

Endocannabinoids are fatty acid derivatives of membrane phospholipid

Anandamide
2-AG

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17
Q

Anadamide

A

Arachidonoyl ethanolamine (AEA)

  • CB1 partial agonist
  • multiple synthetic pathways
  • degraded by FAAH (fatty acid aside hydrolase)
    - very, very nonpolar
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18
Q

2-AG

A

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)
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19
Q

DAG lipase (DGL) converts […]

A

DAG lipase (DGL) converts DAG —> 2-AG

  • increased [Ca2+] by VGCC or NMDA-R
  • GPCR/ PLC (also PLA2 and PLD)
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20
Q

Monoacyl- glycerol lipase (MAGL)

A

Degrades 2-AG

21
Q

Uptake transporter

A

Characterization is incomplete

22
Q

There are 3 different signaling mechanisms used by endocannbinoids

A

Retrograde signaling- usual mode of altering communication
Non-retrograde signaling
- TRPV1- nonspecific cation channels (capsaicin receptor)
Neuron- Astrocytes signaling

23
Q

Retrograde signaling by endocannabinoids is involved in synaptic plasticity

A

Homosynaptic excitatory LTD: released Glu

Heterosynaptic inhibitory LTD: released GABA

24
Q

Pharamcological and genetic techniques are used to determine the roles of CB receptors

A

Ligands

Knock-out mice:
- CB1, CB2, FAAH, or MAGL KO

25
Q

Pharmacological technique ligands

A

CP-55940 and WIN 55212-2: full agonists CB1 and CB2

SR 141716A (rinomabant): selective CB1 antagonist

26
Q

CB1 receptors involved in brain’s reward system:

A
  1. Reductions in rewarding effects of natural substances such as food/ sweetened solutions in animals that lack eCB activity
  2. Enhanced reward due to pharmacological manipulation that increase eCB signaling
27
Q

CB1 receptors mediate many of the effects of TNC and endocannabinoids

A

Resultant effects of THC in mice

  • decreased locomotion
  • hypothermia
  • catalepsy
  • hypoalgesia
28
Q

Functional effects of cannabinoids

A
  • decreased nausea/ vomiting
  • memory/ extinction (impairs episodic, verbal memory and working memory)
  • anxiolytic, antidepressant
  • analgesic
  • decreased seizure
29
Q

4 stages in infrequent THC use

A
  1. Buzz
  2. High
  3. Stoned
  4. Come-down
30
Q

Reinforcement

A

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
31
Q

eCB signaling is anxiolytic and antidepressant

A

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
32
Q

eCB signaling is anxiolytic and antidepressant: increase eCB

A
  • eCBs are anxiolytic in EPM, light-dark test

- inhibition of FAAH prevents anxiety-like behaviors following social defeat stress

33
Q

eCB signaling is anxiolytic and antidepressant: decrease eCB

A
  • CB1 KO show increased anxiety

- mice with disrupted DGLa increases both anxiety and depression

34
Q

DGLa deletion

A
  • reduces 2-AG in PFC, amygdala, and striatum
  • increases anxiety
  • increased anhedonia
35
Q

There is limited evidence that cannabinoids improve symptoms of depression

A

No RCTs have specifically evaluated cannabis in patients with a depressive disorder

  • evidence is inconclusive
36
Q

There is limited evidence that cannabinoids improve symptoms of anxiety

A
  • 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
37
Q

Hyperalgesia is induced by:

A

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
38
Q

Cannabinoids affect the cognitive aspects of pain

A

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
39
Q

There is substantial evidence that cannabis is an effective treatment for chronic pain in adults

A

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
40
Q

The first FDA- approved drug that contains a purified drug substance derived from marijuana

A

Epidiolex

  • Lennox-Gastaut syndrome
  • Dravet syndrome
41
Q

The addiction potential of THC

A
  • humans and squirrel monkeys self-administer THC

- rodents and Theseus monkeys do NOT

42
Q

THC self-administration: role of CB1

A
  • blocked by SR141716A

- 2-AG is also self-administered

43
Q

Cannabinoids are atypical drugs of abuse

A

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

44
Q

Amotivational Syndrome

A

State of relaxed and careless drifting after significant marijuana use

45
Q

Cannabinoids act on CB1 receptors on GABAergic interneurons in the VTA to inhibit GABA release

A

CB1-R in VTA

  • hyperpolarize IN
  • decrease GABA release
  • increase VTA firing
  • increase DA release
46
Q

CB1 and MOP receptors seem to work together

A

MOR in VTA

  • increased DA release
  • CBS lose rewarding properties in MOR-KO
47
Q

Chronic CB administration leads to tolerance and precedes precipitated withdrawal: Tolerance

A
  • CB1 desensitization

- CB1 down-regulation

48
Q

Chronic CB administration leads to tolerance and precedes precipitated withdrawal: Withdrawal

A
  • Precipitated with SR 141716A
  • decreased DA neuron firing
  • increased CRF release in CeA
  • increased stress hormones (ex. Corticosterone)
49
Q

Precipitated Withdrawal

A

Administration of antagonist would abruptly block receptors despite continued presence of THC

Neuropharmacology (15 decks)

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