Endocannabinoids Flashcards
What are endocannabinioids?
- 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
Describe CB1 and CB2
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
Describe CB1 receptors
- Inhibitory through effects on adenylate
cyclase (↓ cAMP), GIRK (↑ K+ efflux),
and Ca2+-channels (↓ Ca2+ influx) - CB1 receptors are exclusively
expressed presynaptically
Deescribe endocannabinoids
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.
Describe endocannbinoid synthesis
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).
Describe retrograde signalling
- 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
Describe depolarization induced suppression of inhibition
- Post-synaptic depolarization can
activate endocannabinoid synthesis - Endocannabinoids are released and
supress presynaptic GABA release
Describe metabolism of endocannabinioids
- Two key enzymes are responsible for
the breakdown of endocannabinoids - Fatty-acid amide hydrolase (FAAH)
metabolizes anandamide - Monoacylglycerol lipase (MAGL)
metabolizes 2-AG
Describe endocannabinoid breakdown
- 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
Describe stress and anxiety
- 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
Describe HPA axis regulation
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.
describe limbic control of HPA axis
Under steady-state conditions
CB1 antagonism results in an
increase in glucocorticoid release
Direct microinjection into the
basolateral amygdala (BLA)
increases glucocorticoid release
Describe anandamine’s role in stress response
- 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.
Describe negative feedback
Glucocorticoids can act directly on the
hypothalamus or pituitary to provide
negative feedback preventing excess
glucocorticoid release
- 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
Describe endocannabinoids in stress response
- 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
- 2-AG synthesis in the PFC and HC
