PSYCH 478 > Endocannabinoids > Flashcards

Endocannabinoids Flashcards

(53 cards)

Study These Flashcards
1
Q

What are the 2 receptors for cannabinoids found in humans? Where are they found?

A
  • CB1 in CNS
  • CB2 on immune cells and microglia
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2
Q

What is CB3 receptor proposed for?

A

CBD

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3
Q

What mechanism do cannabinoid receptors use?

A

GPCR
- most Gi
- rarely Gs

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4
Q

CB1 receptor expression in the postnatal day 14 mouse brain shows extensive expression throughout the brain with conspicuous absence in ____________

A

the thalamus

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5
Q

What is the mechanism of CB1 receptors? Where are they exclusively expressed?

A
  • primarily Gi
  • adenylate cyclase (decrease cAMP), GIRK (increase K+ efflux), and Ca2+ channels (decrease Ca2+ influx)
  • presynaptic (glutamatergic, GABAergic, and monoaminergic nerve terminals)
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6
Q

THC is a specific ______ ______ of the CB receptors.

A

partial agonist

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7
Q

How many endocannabinoids have been identified?

A

6

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8
Q

What are the best described endocannabinoids in the CNS? Which one was identified first?

A
  • anandamide (first)
  • 2-AG
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9
Q

TRUE or FALSE: endocannabinoids are lipophobic like phytocannabinoids

A

FALSE: both are lipophilic

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10
Q

TRUE or FALSE: endocannabinoids DO NOT function as classic NTs

A

TRUE

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11
Q

What is the primary function of endocannabinoids? How does it do this?

A
  • primary function = retrograde signalling to modulate presynaptic NT release through ACTIVITY-DEPENDENT SYNTHESIS
  • does this by freely diffusing across membranes
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12
Q

TRUE or FALSE: endocannabinoids cannot be packaged into secretory vesicles

A

TRUE

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13
Q

Describe endocannabinoid synthesis.

A
  • endocannabinoids formed from phospholipids
  • PIP2 –PLC–> IP3+DAG –DAGL–> 2AG
  • phospholipid –PLA2/C/D–> anandamide
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14
Q

What is depolarization-induced suppression of inhibition? Explain how endocannabinoids regulate it.

A
  • form of short-term synaptic plasticity
  • post-synaptic depolarization can activate endocannabinoid synthesis
  • endocamabinoids suppress presynaptic GABA release –> net decrease in inhibitory transmission leads to increased output from cell
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15
Q

What are the 2 key enzymes responsible for the breakdown of endocannabinoids? What is their function?

A
  • FAAH metabolizes anandamide
  • MAGL metabolizes 2-AG
  • both attenuate endocannabinoid signalling
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16
Q

A common genetic variant in FAAH (P129T) __________ the rate of breakdown of anandamide

A

decreases

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17
Q

In humans carrying the FAAH mutation, there is _____ anxiety and _______ fear extinction.

A

Decreased anxiety; increased fear extinction

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18
Q

Slide 10 effects of FAAH variant in rats vs humans

A

go look

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19
Q

endocannabinoids are highly involved in regulation of the physiological response to _____________________.

A

psychological stressors

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20
Q

What are the 2 pathways that acute stress activates?

A
  • NEURONAL RESPONSE - activation of sympathetic NS via descending paths from hypothalamus
  • NEUROENDOCRINE RESPONSE - activation of the HPA axis leading to release of glucocorticoid hormones
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21
Q

TRUE or FALSE: In many systems anandamide functions as a phasic (on demand) regulator of activity
while 2-AG functions as a tonic (steady-state) regulator.

A

FALSE: anandamide is tonic; 2AG is phasic

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22
Q

explain hpa axis regulation

23
Q

Describe limbic control of the HPA axis.

Study These Flashcards
A
  • under steady-state conditions CB1 antagonism results in an increase in GC release
  • direct microinjection into basolateral amygdala (BLA) only increases GC release
  • BLA projections indirectly excite PVN

SEE SLIDE 13 for more details

24
Q

TRUE or FALSE: CB1 agonists to the BLA suppress stress-induced activation of the HPA axis

25
Under conditions of stress, _______ levels in the BLA drop as a result of _______________ _____________
anandamide; FAAH induction
26
TRUE or FALSE: decreased anandamide levels induces inhibitory tone, leading to inhibitory output to the PVN
FALSE: release inhibitory tone, excitatory output
27
TRUE or FALSE: RAPID negative feedback of GC can be blocked by microinjection of CB1 antagonists, whereas SLOW negative feedback involves the limbic system
TRUE
28
Explain negative feedback of HPA axis.
slide 15 diagram GCs can act directly on hypothalamus/pituitary to provide negative ffedback prevneting excess GC release
29
How do endocannabinoids modulate activation in response to stress? recovery from stress?
modulate activation: - AEA (-) amygdala activation - FAAH releases AEA inhibitory tone on stress (i.e. increase GC release) modulate recovery: - 2AG synthesis in PVN --> RAPID negative feedback - 2-AG syntehsis in PFC and HC --> SLOW neg feedback
30
what is the role of endocannabinoids in appetite?
- CB-1 initiate orexigenic effects in PVN, downstream of ghrelin - GHSR signalling induces DAGL activity - 2-AG syntehsis increases and signals to presynaptic CB-1 receptors - CB-1 antagonists decrease appetite - CB-1 agonists increase appetite
31
CB-1 antagonists can _______ the orexigenic effects of ghrelin
block
32
TRUE or FALSE: CB-1 antagonists induce the munchies
FALSE: agonists
33
Describe the effects if cannabis on the acute stress response
see slide 18 table (BP, thirst, hunger, anxiety, locomotion)
34
TRUE or FALSE: CBD has a low affinity for CB receptors
TRUE
35
How does CBD act at CB1 and CB2 receptors? How does it affect THC? What is another receptor it also acts at and what are the effects of binding? What enzyme might it inhibit?
- weak CB1 antagonist - CB2 inverse agonists - potentiate THC at CB1 - 5-HT1A receptor agonist (antidepressant/anxiolytic effects) - inhibit FAAH
36
What are the therapeutic effects of CBD/high-CBD?
- high CBD = anticonvulsant for treatment-resistant epilepsy - CBD = antipsychotic effects in animal schizophrenia - CBD = antioxidant (neuroprotective) against ischemic stroke
37
In human trials, CBD co-administration prevents the adverse effects of ____________________.
THC or CB1 agonist administration (e.g. hallucinations and psychosis)
38
Selective breeding of cannabis for recreational use has resulted in current strains being __________ – this trend is being reversed by current medical marijuana producers
high THC, low CBD
39
Describe rimonabant as a CB1 psychotherapeutic.
- synthetic CB1 antagonist - orexilytic
40
Describe nabilone as a CB1 psychotherapeutic.
- synthetic THC analogue (PO) - antiemetic - adjunct analgesic for neuropathic pain
41
Describe dronabinol as a CB1 psychotherapeutic.
- THC, PO - antiemetic - orexigenic
42
Describe naboximol/sativex as a CB1 psychotherapeutic.
- THC:CBD, 1:1 - mouth spray - treat MS symptoms including spasticity and neuropathic pain???
43
Treatment with rimonabant results in transient _______ of food intake, but _______________ in body weight in mice fed high-fat diet.
reduction; sustained decrease
44
What are 4 FAAH inhibitors? What is the significance of each?
- Bial - failed due to serious adverse events - Janssen - treat anxiety and depression, but suspended after Bial events - Sanofi - failed for depression; ongoing for cancer pain - Vernalis - trials for neuropathic pain
45
Describe what we know about cannabis tolerance
- in animals, THC --> decreased CB1 receptor - long-term heavy users self-report decreased high - patterns of escalating drug use are diminished
46
What do we know about cannabis dependence?
PSYCHOLOGICAL (not physiological) dependence may drive addiction
47
Describe self-administration of THC in animal models.
- often produce aversive stimulus initially - squirrel monkeys first trained on cocaine demonstrate THC self-admin
48
How does THC affect mesolimbic dopamine? How do we know these mechanisms may be dependent on opioid receptors?
- THC increases VTA firing rates and DA release in NAc - NALTREXONE abolishes THC self-administration and blocks NAc DA release in ANIMALS - aversive effects of THC abolisehd with KOR KO mice -
49
what is the difference in THC effects with naltrexone administration for humans vs animals?
- animals: decrease THC self-admin and block NAc DA release - humans: increase positive subjective effects of inhaled THC admin in regular heavy marijuana users
50
What are the withdrawal symptoms of cannabis?
- irritability - anxiety - depressed mood - sleep difficulties - decreased appetite
51
What are the key indicators of cannabis dependence in humans?
- craving - difficulty stopping
52
how can THC withdrawal be precipitated in animals? How does it present?
- administration of CB1 antagonist after prolonged admin - wet-dog shakes, excessive self-grooming, hyperactivity
53
What are the 2 models of cannabis-induced psychosis?
1. adolescent cannabis use is causal in developing psychosis in vulnerable individuals 2. preclinical changes in schizophrenia predispose people to drug use
PSYCH 478
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