Topic 27: Endocannabinoids Flashcards
What are cannabinoid receptors?
THC was first isolated in 1964
the receptor responsible for THC binding was only identified in 1988: significant THC binding was observed in the cortex, basal ganglia, hippocampus, and cerebellum
in 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
What are CB1 receptors in the CNS?
two receptors for cannabinoids are found in humans:
CB1 is expressed widely in the CNS
CB2 is expressed primarily on immune cells: only in microglia in the CNS
cannabinoid receptors are G-protein coupled receptors: most Gi-coupled, rarely Cs-coupled
putative CB3 receptor for CBD recently proposed: GPR55 antagonist
What are the characteristics of CB1 receptors?
CB1 receptors are G-protein coupled, primarily to Gi
inhibitory through effects on adenylate cyclase (decreased cAMP), GIRK (increased K+ efflux), and Ca2+ channels (decreased Ca2+ influx)
CB1 receptors are exclusively expressed presynaptically: present on glutamatergic, GABAergic, and monoaminergic nerve terminals
What are endocannabinoids?
THC is a specific partial agonist of the CB receptors
endocannabinoids are the endogenous ligands for the CB receptors, 6 putative endocannabinoids have been identified
anandamide was first identified in 1992
2-AG was identified in 1994-5; these two endocannabinoids are the best described in the CNS
like phytocannabinoids (from plants), endocannabinoids are highly lipophilic
What is the retrograde signaling of endocannabinoids?
endocannabinoids do not function as classic neurotransmitters
endocannabinoids are capable of free diffusion through membranes: they cannot eb packaged into secretory vesicles
primary function is retrograde signaling to modulate presynaptic neurotransmitter release
release from postsynaptic compartments is through activity-dependent synthesis mechanisms
What is endocannabinoid synthesis?
endocannabinoids are formed from arachidonoyl-containing phospholipids
2-AG is synthesized in activity dependent process (such as Gq signaling to phospholipase C - PLC) from the hydrolysis of diacylglycerol (DAG) by DAG lipase (DAGL)
anandamide is similarly synthesized by cleavage of phospholipids by phospholipases A2, C and D
What are the steps of the 2-AG synthesis?
PIP2 is cleaved by PLC into IP3 and DAG
DAG-lipase converts DAG to 2-AG
What is the depolarization-induced suppression of inhibition?
a specific form of short-term synaptic plasticity
post-synaptic depolarization can activate endocannabinoid synthesis (e.g., dendritic backpropagation of strong stimuli)
endocannabinoids are released and suppress presynaptic GABA release: net decrease in inhibitory transmission leads to increased output from cell
What is the metabolism of endocannabinoids?
two key enzymes are responsible for the breakdown of endocannabinoids
fatty-acid amide hydrolase (FAAH) metabolizes anandamide
monoacyglycerol lipase (MAGL) metabolizes 2-AG
both are normally expressed to attenuate endocannabinoid signaling
activity dependent expression can regulate cannabinoid signaling
What are the genetic variants of FAAH?
a common genetic variant in FAAH (P129T) decreases the rate of breakdown of anandamide (~20% of North Americans): increased level 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 conditioned fear responses: decreased anxiety and increased 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
How are endocannabinoids involved in 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
excess activity of the HPA axis is implicated in a number of psychiatric disorders including depression, anxiety, bipolar
in many systems anandamide functions as a tonic (steady-state) regulator of activity while 2-AG functions as a phasic (on demand) regulator
How is the HPA axis regulated?
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 signaling: 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
What is the limbic control of the HPA axis?
under steady-state conditions CB1 antagonism results in an increase in glucocorticoid release
suggestive of steady-state endocannabinoid suppression of the HPA axis
microinjection of CB1 antagonists into the hypothalamic paraventricular nucleus (PVN) does not affect glucocorticoid release
direct microinjection into the basolateral amygdala (BLA) increases glucocorticoid release
BLA projections indirectly provide excitatory input to the PVN
How is FAAH impacted by the stress response?
under conditions of stress anandamide levels in the BLA drop as a result of FAAH induction
decreased anandamide levels release inhibitory tone leading to excitatory output to the PVN
CB1 agonists administered to the BLA suppress stress-induced activation of the HPA axis
What is the quick negative feedback pathway of glucocorticoids?
rapid feedback in the PVN can be blocked by microinjection of CB1 antagonists
role of endocannabinoids in controlling negative feedback
What is the slow negative feedback pathway of glucocorticoids?
slower mechanisms for negative feedback involve the limbic system
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
How do endocannabinoids modulate activation in response to stress?
AEA inhibits amygdala activation
FAAH induction releases AEA inhibitory tone on stress
How do endocannabinoids modulate recovery from 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
How are endocannabinoids involved in appetite?
CB1 is proposed to function downstream of ghrelin to initiate orexigenic effects in the PVN
GHSR signaling (via Gq, PLC, PKC) induces DAGL activity
2-AG synthesis increases and signals to presynaptic CB1 receptors
CB1 antagonists can block the orexigenic effects of ghrelin
CB1 agonism notably increases appetite, increases craving for highly rewarding food, and increased hedonic value of food
“munchies”
What is cannabidiol?
in contrast to THC, CBD has a distinct pharmacological profile
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 B1 receptor by unknown mechanisms
CBD is also a 5-HT1A receptor agonist: contribute to antidepressant and anxiolytic effects
possible inhibitor of FAAH
What are the therapeutic effects of CBD?
CBD or high-CBD strains of cannabis have been developed for therapeutic use
high CBD cannabis is being explored as an anti-convulsant for treatment resistant epilepsy
CBD has marked antipsychotic effects in animal models of schizophrenia
CBD is a potent antioxidant and has been shown to neuroprotective in models of ischemic stroke
selective breeding of cannabis for recreational use has resulted in current strains being high-THC, low-CBD but this trend is being reversed by current medical marijuana producers
What is Rimonabent?
synthetic CB1 antagonist
orexilytic
What is Nabilone?
synthetic THC analogue (PO)
antiemetic, adjunct analgesic for neuropathic pain
What is Dronabinol?
THC, PO
antiemetic, orexigenic
