Endocannabinoids Flashcards

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1
Q

What are endocannabinioids?

A
  • By 1990 researchers had cloned the gene for the
    brain cannabinoid receptor (termed CB1 receptor)
  • Endogenous ligands for the cannabinoid
    receptors (endocannabinoids) were first
    identified in 1992
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2
Q

Describe CB1 and CB2

A

CB1 is expressed widely in the CNS
» CB2 is expressed primarily on immune cells
‒ Only microglia in the CNS

Putative CB3 receptor for CBD recently

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3
Q

Describe CB1 receptors

A
  • Inhibitory through effects on adenylate
    cyclase (↓ cAMP), GIRK (↑ K+ efflux),
    and Ca2+-channels (↓ Ca2+ influx)
  • CB1 receptors are exclusively
    expressed presynaptically
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4
Q

Deescribe endocannabinoids

A

THC is a specific partial agonist of the CB receptors.

Anandamide was first identified in 1992 and named
from the Sanskrit word ananda, meaning ‘bliss’.

2-AG was identified in 1994-5. These two
endocannabinoids are the best described in the
CNS.

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5
Q

Describe endocannbinoid synthesis

A

Endocannabinoids are formed from
arachidonoyl-containing phospholipids
(arachidonic acid is an essential ω6 fatty acid
found in peanut oil).

2-AG is synthesized in activity dependent
processes (such as Gq signalling to
phospholipase C - PLC) from the hydrolysis of
diacylglycerol (DAG) by DAG lipase (DAGL).

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5
Q

Describe retrograde signalling

A
  • Endocannabinoids do not function as classic
    neurotransmitters
  • Endocannabinoids are capable of free diffusion
    through membranes
  • They cannot be packaged into secretory vesicles
  • Primary function is retrograde signalling to
    modulate presynaptic neurotransmitter release
  • Release from postsynaptic compartments is
    through activity-dependent synthesis
    mechanisms
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6
Q

Describe depolarization induced suppression of inhibition

A
  • Post-synaptic depolarization can
    activate endocannabinoid synthesis
  • Endocannabinoids are released and
    supress presynaptic GABA release
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7
Q

Describe metabolism of endocannabinioids

A
  • Two key enzymes are responsible for
    the breakdown of endocannabinoids
  • Fatty-acid amide hydrolase (FAAH)
    metabolizes anandamide
  • Monoacylglycerol lipase (MAGL)
    metabolizes 2-AG
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8
Q

Describe endocannabinoid breakdown

A
  • FAAH
  • A common genetic variant in FAAH (P129T) decreases the rate of breakdown of anandamide (~20% of
    North Americans)
  • Increased levels of anandamide throughout the brain
  • FAAH P129T variant is associated with a greatly reduced risk of anxiety disorder and PTSD
  • FAAH P129T mice show decreased anxiety in tests such as the elevated plus maze and more rapid
    extinction of conditioned fear responses
  • Anxiety ↓ and fear extinction ↑ in humans carrying the mutation
  • FAAH P129T is also overrepresented in problem users of street drugs, suggesting increased risk of
    drug and alcohol abuse
  • BUT associates with decreased craving and withdrawal in cannabis users
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9
Q

Describe stress and anxiety

A
  • Endocannabinoids are highly involved in regulation of the physiological response to
    psychological stressors
  • Acute stress activates two distinct pathways:
  • Neuronal response – activation of the sympathetic nervous system via descending pathways from
    hypothalamus
  • Neuroendocrine response – activation of the hypothalamic-pituitary-adrenal axis (HPA axis) leading
    to release of glucocorticoid hormones
  • In many systems anandamide functions as a tonic (steady-state) regulator of activity
    while 2-AG functions as a phasic (on demand) regulator
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10
Q

Describe HPA axis regulation

A

Hypothalamic release of CRH leads to pituitary
release of ACTH into circulation, and stimulates
adrenal release of cortisol.

Negative feedback is provided by cortisol to
the hypothalamus to attenuate stress signalling
– this feedback process may be impaired in
depression and anxiety disorders.

The limbic system provides a number of
modulatory inputs to the hypothalamus that are
critical in HPA response to psychological
stressors.

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11
Q

describe limbic control of HPA axis

A

Under steady-state conditions
CB1 antagonism results in an
increase in glucocorticoid release

Direct microinjection into the
basolateral amygdala (BLA)
increases glucocorticoid release

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12
Q

Describe anandamine’s role in stress response

A
  • Under conditions of stress
    anandamide levels in the BLA drop as
    a result of FAAH induction.
  • Decreased anandamide levels release
    the inhibitory tone leading to
    excitatory output to the PVN.
  • CB1 agonists administered to the BLA
    supress stress-induced activation of
    the HPA axis.
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13
Q

Describe negative feedback

A

Glucocorticoids can act directly on the
hypothalamus or pituitary to provide
negative feedback preventing excess
glucocorticoid release

  1. Rapid feedback in the PVN can be
    blocked by microinjection of CB1
    antagonists

2-AG levels increase resulting in inhibition
of GABA interneurons
Cortical output to the BNST is disinhibited
Net increase in inhibitory output from the
BNST to the PVN attenuates stress response

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14
Q

Describe endocannabinoids in stress response

A
  • AEA inhibits amygdala activation
  • FAAH induction releases AEA
    inhibitory tone on stress
  • 2-AG synthesis in the PVN contributes to
    rapid negative feedback
    • 2-AG synthesis in the PFC and HC
      contribute to slow negative feedback
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15
Q

Describe endocannabinoids in appetite

A
  • CB-1 is proposed to function downstream of
    ghrelin to initiate orexigenic effects in the PVN
  • GHSR signalling (via Gq, PLC, PKC) induces
    DAGL activity
  • 2-AG synthesis increases and signals to
    presynaptic CB-1 receptors
  • CB-1 antagonists can block the orexigenic effects
    of ghrelin
  • CB-1 agonism notably increases appetite,
    increases craving for highly rewarding foods, and
    increases hedonic value of food
  • ‘Munchies’
16
Q

Describe cannabidiol

A
  • CBD has a very low affinity for CB receptor
  • CBD is a weak CB1 antagonist and a CB2 inverse
    agonist but may act indirectly
  • CBD paradoxically potentiates the effects of THC
    at the CB1 receptor by unknown mechanisms
  • CBD is also a 5-HT1A receptor agonist
  • Contribute to antidepressant and anxiolytic effects
  • Possible inhibitor of FAAH
17
Q

Describe therapeutic effects of CBD

A

High CBD cannabis is being explored as an anti-convulsant for treatment resistant epilepsy
(such as Dravet syndrome)

  • CBD has marked antipsychotic effects in animal models of Schizophrenia
  • CBD is a potent antioxidant and has been shown to be neuroprotective in models of ischemic
    stroke
  • Selective breeding of cannabis for recreational use has resulted in current strains being high-
    THC, low-CBD– this trend is being reversed by current medical marijuana producers
18
Q

Describe CB1 psychotherapeutics

A
  • Rimonabant– synthetic CB1 antagonist – orexilytic
  • Nabilone– synthetic THC analogue (PO) – antiemetic,
    adjunct analgesic for neuropathic pain
  • Dronabinol (THC, PO) – antiemetic, orexigenic
  • Naboximol/Sativex (THC/CBD ~ 1:1) – mouth spray –
    MS symptoms incl. spasticity, neuropathic pain
19
Q

Describe FAAH inhibitors

A

FAAH inhibitors (experimental)
* Bial– BIA 10-2474 – serious adverse events in a
2016 phase I trial left 1 participant dead and 4 with
permanent neurological impairments –
determined likely due to poor drug and trial
design (low affinity, multiple high doses, and
bioaccumulation of the drug)

  • Janssen– JNJ-42165279 – phase II trials for
    anxiety/depression suspended after Bial’s adverse
    events
  • Sanofi– SSR-411298 – failed in a trial for
    depression, ongoing trials for cancer pain
  • Vernalis– V-158866 – phase I trials for neuropathic pain
20
Q

Describe cannabis tolerance and dependence

A
  • In animals, THC administration results in
    decreased CB1 receptor expression
  • Many suggest psychological, not physiological
    dependence drives addictions (e.g. behavioural
    tolerance rather than pharmacodynamic tolerance)
21
Q

Describe self-administration in animal models

A
  • THC administration often produces an
    aversive stimulus initially in animals
  • THC self-administration has been
    demonstrated in squirrel moneys
    first trained on the operant
    procedure with cocaine
22
Q

Describe mesolimbic dopamine

A
  • The mechanisms may be dependent
    on opioid receptors (animal models)
  • Naltrexone abolishes THC self-
    administration and blocks NAc
    dopamine release
  • Aversive effects of THC
    administration are abolished in κ-
    opioid receptor knockout mice
  • However, in human trials naltrexone
    administration increased the
    positive subjective effects of
    inhaled THC administration in
    regular heavy marijuana users
23
Q

Describe cannabis withdrawal

A
  • THC withdrawal can be precipitated in animals
  • Administration of CB1 antagonist after period of prolonged
    administration
  • Wet-dog shakes, excessive self-grooming, hyperactivity
24
Q

Describe cannabis-related psychosis

A
  • A major concern with the use of cannabis is the
    occurrence of psychosis
  • Cannabis use (particularly during adolescence) is
    associated with an increased risk of psychosis
  • Alcohol, cannabis, amphetamine, or cocaine use
    is often a precipitant for the first psychotic
    episode in schizophrenia
  • Cannabis use interacts with genetic risk factors
    for SCZ