Mechanism of Ketamine as an Antidepressant Flashcards
Depression (4)
➢ ~7% of U.S. population suffer from major depressive disorder yearly
➢ Leading cause of disability worldwide
➢ ~30% of patients do not respond to conventional antidepressants
➢ 800,000 deaths due to suicide yearly
Rapid antidepressant effects of sub-anesthetic doses
of ketamine in humans (3)
used in animals
accidentally found in humans
even a very low dose = dec. in depressive scores compared to placebo
= prototype
Does NMDAR inhibition underlie the antidepressant
actions of ketamine in mice? (4)
mice - r ket + s-ket:
- s-ket = most potent NMDA r inhib
- r ket = less potent
if inhib underlies antidepressant action = s-ket should be the best
= s -ket has no antidepress action in 24hr , r-ket shows some at 10 + 30mg/kg
=NMDAR inhibition might not be the primary mechanism
underlying ketamine’s antidepressant actions
Ketamine is rapidly metabolized by liver CYP450 enzymes after administration (3)
metabolised into multiple metabolites:
- most important= norket (NMDAr in) = induces anaesthetic effects
- dehdronorket does crosses BBB = X
- hydroxynorket’s (HNK’s) cross BBB in animals + humans
Deuterated ketamine: Reducing metabolism to (2S,6S;2R,6R)-HNK (4)
1) replaced h w/ deuterium molecules
= slows down rate of metab
won’t be diff to ket- only diff will be the dec . in metab of ket to hnk
= ket levels the same
used 2 drugs to check inhib/blocking = ket = anti-depress + deteriorated ket (can’t metabolise to hnk) couldn’t
= Metabolism of ketamine to its HNK metabolites is critical
for its antidepressant-like actions
(2R,6R)-HNK exerts robust antidepressant-relevant actions in rodent tests (2)
just HNK works?
- a lot to studies
= see rats go to the middle (not in shadows) = good results
=HNK is required and sufficient to exert ketamine’s antidepressant-like actions
Lack of effects of (2R,6R)-HNK on NMDAR inhibition-
mediated adverse effects
side effects:
- motor coord
- self-admin = abuse
=HNK does not seem to exert ketamine-related side effects (at least in animal models)
(2R,6R)-HNK is not an NMDAR antagonist at
antidepressant-relevant doses in vivo (3)
drug discrimination - subjective effects of teh drug
- food pellet (training)
- ket + saline injections
- with mice HNK couldn’t feel Ket = didn’t press lever as much
= HNK didn;t feel like NMDr inhib in-vivo
(2R,6R)-HNK is not an NMDAR antagonist at antidepressant-
relevant concentrations in vitro
Huge conc’s of HNK are needed to block the NMDAR
=(2R,6R)-HNK DOES NOT INHIBIT THE NMDAR TO EXERT ITS ANTIDEPRESSANT-RELEVANT ACTIONS
(2R,6R)-HNK acts presynaptically to enhance glutamatergic
synaptic transmission (SC-CA1 pathway) (4)
anti-depress require synaptic plasticity - they require strengthening b/w neurones
HNK: inc. AMPAR- related responses electrophysiologically = mediated pre-synaptically : inc. in glutamatergic neurotrans
Effect of ketamine and (2R,6R)-HNK on AMPA receptor subunits: western blots - measuring kevels of glutamate r - AMPAR r in hippo
= 24hrs in HNK similar to ket - incr pain r’s = simialr to healthy p LT potentiation = strengthening of sinuses
(2R,6R)-HNK’s antidepressant effects requires AMPA
receptor activity
HNK red. immobility line = uses anti-depress effect
(2R,6R)-HNK enhances cortical high-frequency
(30-80 Hz; gamma) EEG power (3)
rapid antidepress action involved ket activation of pre-frontal cortex in form of = incr’s in high freq oscillation
Measure EEG: inc in gamma power + high freq oscillations in frontal cortex = indication of activation of cortical neurons (Ventra hippo)
= HNK inc gamma power =HNK’s actions require AMPAR activation
What might regulate the presynaptic actions of (2R,6R)-HNK? (2)
pre-synap inc of Glutamate after HNK admin
mGlu1/2 in ket reg = tested mGLu for HNK
mGlu2/3R agonist pre-treatment prevents (2R,6R)-HNK’s
antidepressant-relevant actions (2)
it was able to prevent antidepress actions of HNK + prevent actions to inc gamma power in EEG
- showed mGlu3 is used not Mglu2 - but no direct links
=Convergent mechanism of HNK action with mGlu2R signalling(downstream - not r level)
Proposed mechanism of (2R,6R)-HNK action (6)
1) HNK enters + crosses BBB
2) through a mech that converges w/ mGlu2 sign. = induces AP presynap
3) = inc. glut levels in synaptic cleft
4) glut bind to AMPAR r’s = activate them
5) = inc. in BDF release (synap molecule- synaptic plasticity + antidepress action)
6) downstream mech = activate rapamycin complex (synap plastic) = protein synthesis = strengthens synapse
