Endocannabinoids Flashcards
1
Q
Significant THC binding was observed in the
A
cortex, basal ganglia, hippocampus, and
cerebellum
2
Q
By 1990 researchers had cloned the gene for the
brain cannabinoid receptor (termed
A
CB1
receptor)
3
Q
(endocannabinoids)
A
Endogenous ligands for the cannabinoid
receptors
4
Q
Two receptors for cannabinoids are found
in humans
A
CB1
CB2
5
Q
CB1
A
expressed widely in the CNS
6
Q
CB2
A
is expressed primarily on immune cells
7
Q
CB2 CNS
A
Only microglia in the CNS
8
Q
Cannabinoid receptors are
A
G-protein
coupled receptors
9
Q
Cannabinoid receptors are G-protein
coupled receptors
A
Mostly Gi - coupled
Rarely Gs - coupled
10
Q
CB3
A
receptor for CBD recently proposed
11
Q
Putative CB3
receptor for CBD recently proposed
A
GPR55 - antagonist
12
Q
CB1receptors are
A
G-protein coupled
13
Q
CB1
receptors are exclusively
expressed
A
presynaptically
14
Q
CB1
receptors are G-protein coupled - primarily
A
Gi
15
Q
CB1 Inhibitory through effects on
A
adenylate cyclase (↓ cAMP)
GIRK (↑ K+ efflux)
Ca2+-channels (↓ Ca2+ influx)
16
Q
CB1 receptors are exclusively expressed presynaptically - Present on (3)
A
glutamatergic, GABAergic,
and monoaminergic nerve terminals
17
Q
THC is a specific
A
partial agonist of the CB receptors.
18
Q
Endocannabinoids are the
A
endogenous ligands for
the CB receptors
19
Q
Endocannabinoids (2)
A
Anandamide
2-AG
20
Q
Like phytocannabinoids (from plants),
endocannabinoids are
A
highly lipophilic
21
Q
Endocannabinoids do not function as
A
classic
neurotransmitters
22
Q
Endocannabinoids are capable of
A
free diffusion
through membranes
23
Q
Endocannabinoids are capable of free diffusion
through membranes
A
They cannot be packaged into secretory vesicles
24
Q
Primary function is
A
retrograde signaling to
modulate presynaptic neurotransmitter release
25
Release from postsynaptic compartments is
through
activity-dependent synthesis
mechanisms
26
Endocannabinoid
synthesis
Endocannabinoids are formed from
arachidonoyl-containing phospholipids
27
creation of 2-AG
PIP2-- PLC-> DAG --DAGL-> 2-AG
28
Anandamide is similarly synthesized by
cleavage of phospholipids by phospholipases
A2, C, and D.
29
Post-synaptic depolarization can
activate
endocannabinoid synthesis
30
Endocannabinoids are released and
supress presynaptic GABA release
31
Endocannabinoids are released and
supress presynaptic GABA release
Net decrease in inhibitory transmission
leads to increased output from cell
32
Two key enzymes are responsible for
the breakdown of endocannabinoids
FAAH
MAGL
33
FAAH
metabolizes anandamide
34
MAGL
metabolizes 2-AG
35
A common genetic variant in FAAH (P129T)
decreases the rate of breakdown of anandamide
36
FAAH P129T variant is associated with a
a greatly reduced risk of anxiety disorder and PTSD
37
FAAH P129T mice show
decreased anxiety in tests such as the elevated plus maze and more rapid extinction of conditioned fear responses
38
FAAH P129T is also overrepresented in
problem users of street drugs, suggesting increased risk of
drug and alcohol abuse
39
Endocannabinoids are highly involved in regulation of the
physiological response to psychological stressors
40
Acute stress activates two distinct pathways
Neuronal response
Neuroendocrine response
41
Neuronal response
activation of the sympathetic nervous system via descending pathways from
hypothalamus
42
Neuroendocrine response
activation of the hypothalamic-pituitary-adrenal axis (HPA axis) leading to release of glucocorticoid hormones
43
Excess activity of the HPA axis is implicated in a number of
psychiatric disorders
including depression, anxiety, bipolar
44
In many systems anandamide functions as a
tonic (steady-state) regulator of activity
while 2-AG functions as a phasic (on demand) regulator
45
HPA Axis
regulation
Hypothalamic release of CRH leads to pituitary
release of ACTH into circulation, and stimulates
adrenal release of cortisol
46
HPA Axis
regulation - negative feedback
provided by cortisol to
the hypothalamus to attenuate stress signalling
– this feedback process may be impaired in
depression and anxiety disorders.
47
The limbic system provides a number of
modulatory inputs to the hypothalamus that are
critical in HPA response to psychological
stressors.
48
Under steady-state conditions
CB1 antagonism results in
an
increase in glucocorticoid release
49
BLA projections indirectly
provide
excitatory input to the
PVN
50
Under conditions of stress
anandamide levels in the BLA
drop as
a result of FAAH induction.
51
Decreased anandamide levels release
the
inhibitory tone leading to
excitatory output to the PVN
52
CB1 agonists administered to the BLA
supress stress-induced activation of
the HPA axis
53
Negative feedback limbic system
Glucocorticoids can act directly on the
hypothalamus or pituitary to provide
negative feedback preventing excess
glucocorticoid release
54
Rapid feedback in the PVN can be
blocked by microinjection of
CB1
antagonists
55
negative feedback - 2-AG levels increase resulting in
inhibition
of GABA interneurons
56
negative feedback - Cortical output to the BNST is
disinhibited
57
negative feedback - Net increase in inhibitory output from the
BNST to the PVN attenuates stress response
58
* Endocannabinoids modulate activation
in response to
Stress
59
AEA inhibits
amygdala activation
60
FAAH induction
releases AEA
inhibitory tone on stress
61
Endocannabinoids modulate recovery
from
stress
62
2-AG synthesis in the PVN contributes to
rapid negative feedback
63
2-AG synthesis in the PFC and HC
contribute to
slow negative feedback
64
CB-1 is proposed to function downstream of
ghrelin to initiate orexigenic effects in the PVN
65
GHSR signalling
induces
DAGL activity
66
2-AG synthesis increases and signals to
presynaptic
CB-1 receptors
67
CB-1 antagonists can block the
orexigenic effects
of ghrelin
68
* CB-1 agonism notably increases
appetite,
increases craving for highly rewarding foods, and
increases hedonic value of food
69
The role of endocannabinoids in stress recovery is supported (at
least anecdotally) by
the intoxicating effects of cannabis
70
Acute stress response - Increased blood pressure - effects of cannabis
Decreased blood pressure
71
Acute stress response - increased sweating, water resorption
in kidneys - effects of cannabis
Increased thirst
72
Acute stress response - Decreased gastric function,
mobilization of glucose - effects of cannabis
Increased hunger
73
Acute stress response - Heightened awareness - anxiety - effects of cannabis
Anxiolysis, relaxation
74
Acute stress response - Increased locomotion - effects of cannabis
Decreased locomotion
75
Cannabidiol has a very low affinity for
CB receptor
76
* CBD is a weak CB1 ______ and a CB2 _____
CBD is a weak CB1 antagonist and a CB2
inverse
agonist but may act indirectly
77
CBD paradoxically
potentiates the effects of THC
at the CB1 receptor by unknown mechanisms
78
CBD is also a
a 5-HT1A receptor agonist
79
CBD is also a 5-HT1A receptor agonist
Contribute to antidepressant and anxiolytic effects
80
Cannabidiol Possible inhibitor of
FAAH
81
CBD or high-CBD strains of cannabis have been developed for
therapeutic use
82
High CBD cannabis is being explored as an
anti-convulsant for treatment resistant epilepsy
(such as Dravet syndrome)
83
CBD has marked
antipsychotic effects in animal models of Schizophrenia
84
CBD is a potent
antioxidant and has been shown to be neuroprotective in models of ischemic
stroke
85
Rimonaban
synthetic CB1 antagonist – orexilytic
86
Nabilone
synthetic THC analogue (PO) – antiemetic,
adjunct analgesic for neuropathic pain
87
Dronabinol
(THC, PO) – antiemetic, orexigenic
88
Naboximol/Sativex
(THC/CBD ~ 1:1) – mouth spray –
MS symptoms incl. spasticity, neuropathic pain
89
CB1 Psychotherapeutics (4)
Rimonabant
Nabilone
Dronabinol
Sativex
90
FAAH inhibitors (4)
Bial
Janssen
Sanofi
Vernalis
91
Bial
killed participant
92
Janssen
phase II trials for
anxiety/depression suspended after Bial’s adverse
events
93
Sanofi
– failed in a trial for
depression, ongoing trials for cancer pain
94
Vernalis
phase I trials for neuropathic
pain
95
In animals, THC administration results in
decreased CB1
receptor expression
96
Long-term, heavy users of cannabis self report
decreases in the subjective high
97
Many suggest psychological, not physiological
dependence drives
addictions (e.g. behavioural
tolerance rather than pharmacodynamic tolerance)
98
THC administration increases
VTA
firing rates and subsequent
dopamine release in the NAc
99
Naltrexone
abolishes THC selfadministration and blocks NAc
dopamine release
100
Aversive effects of THC
administration are abolished in
κ-opioid receptor knockout mice
101
However, in human trials naltrexone
administration increased the
positive subjective effects of
inhaled THC administration in
regular heavy marijuana users
102
Craving and difficulty stopping use are key indicators of
dependence in humans
103
THC withdrawal can be precipitated in
animals
104
Withdrawal symptoms to cannabis have been described
including
* Irritability
* Anxiety
* Depressed mood
* Sleep difficulties
* Decreased appetite
105
A major concern with the use of cannabis is the
occurrence of
psychosis
106
Cannabis use (particularly during adolescence) is
associated with an increased risk of
psychosis
107
Cannabis use (particularly during adolescence) is
associated with an increased risk of psychosis (2 models)
- Adolescent cannabis use is causal in developing
psychosis / precipitating psychosis in vulnerable
individuals
- Preclinical changes in schizophrenia are likely to predispose towards drug use
108
Like cocaine and amphetamines cannabis can
precipitate psychosis in predisposed patients
109
Alcohol, cannabis, amphetamine, or cocaine use
is often a
precipitant for the first psychotic
episode in schizophrenia
110
Cannabis is neither necessary nor sufficient to
cause
psychosis or schizophrenia
111
* Cannabis use interacts with
genetic risk factors
for SCZ
