Extract 1
Subanesthetic doses of ketamine, an N-methyl-D-aspartic acid (NMDA) antagonist, have a rapid antidepressant effect which lasts for up to 2 weeks. However, the neurobiological mechanism regarding this effect remains unclear.
In the present study, the effects of subanesthetic doses of ketamine on serotonergic systems in conscious monkey brain were investigated.
Five young monkeys underwent four positron emission tomography measurements with [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile ([(11)C]DASB) for the serotonin transporter (SERT), during and after intravenous infusion of vehicle or ketamine hydrochloride in a dose of 0.5 or 1.5 mg/kg for 40 min, and 24 h post infusion. Global reduction of [(11)C]DASB binding to SERT was observed during ketamine infusion in a dose-dependent manner, but not 24 h later.
The effect of ketamine on the serotonin 1A receptor (5-HT1A-R) and dopamine transporter (DAT) was also investigated in the same subjects studied with [(11)C]DASB. No significant changes were observed in either 5-HT1A-R or DAT binding after ketamine infusion.
Microdialysis analysis indicated that ketamine infusion transiently increased serotonin levels in the extracellular fluid of the prefrontal cortex. The present study demonstrates that subanesthetic ketamine selectively enhanced serotonergic transmission by inhibition of SERT activity.
This action coexists with the rapid antidepressant effect of subanesthetic doses of ketamine. Further studies are needed to investigate whether the transient combination of SERT and NMDA reception inhibition enhances each other's antidepressant actions.
Abstract taken from
http://www.ncbi.nlm.nih.gov/pubmed/23880871
Extract 2
Ketamine pharmacodynamics
7. Ketamine and related arylcyclohexylamines produce a wide range of effects mediated by a variety of
pharmacological mechanisms. Primarily, they all act as non-competitive antagonists at N-methyl-D-aspartate
(NMDA) receptors where they bind at the so-called PCP site on the NMDA receptor (Anis, 1983; Roth, 2013).
These receptors, which play a critical role in glutaminergically mediated excitatory neurotransmission, are
believed to be the principal molecular targets for the anaesthetic action of ketamine and for its
psychotomimetic properties. Its reported antidepressant activity has also been attributed to this mechanism in
the brain (Zarate, 2006) and its analgesic properties, in part, to the same mechanism in dorsal horn neurons
(Quibell, 2011).
8. Systemic administration of NMDA receptor antagonists such as ketamine is known to increase the release of
dopamine in the nucleus accumbens region of brain (Matulewicz, 2010), an activity which is typically associated
with addiction liability (Cadoni, 2007). In addition to its action on NMDA receptors, ketamine also acts at
dopamine D2 and 5-HT2A receptors (Kapur, 2002; Waelbers, 2013). Activation of 5-HT2A receptors is thought to
be related to perceptual disorders and hallucinations (Dursun, 1992). At the concentrations employed in human
models, ketamine also shows both a stereospecific high-affinity for mu; delta; and for sigma opioid receptors
(for a review see Kapur, 2002) and it also affects monoamine transporters (Nishimura, 1999). The complex
neurochemical profile of ketamine reflect its actions as a dissociative anaesthetic, psychostimulant and
analgesic.
9. Overall, recent studies suggest that ketamine leads to a state of increased glutamatergic transmission, which is
linked to psychotic disturbances (Kraguljac, 2013; Sos, 2013). Ketamine also enhances the descending inhibiting
serotoninergic pathway and may exert antidepressant effects (Mion, 2013), possibly because of the significance
of glutamatergic pathways in depression. Treatment with NMDA receptor antagonists has shown the ability to
encourage the formation of new synaptic connections and reverse stress-induced neural changes (Zarate, 2013).
However, it has been suggested that there may be a substantial relationship between ketamine antidepressant
and psychotomimetic effects. This relationship could be mediated by the initial steps of ketamine action through
NMDA receptors (Sos, 2013).
10. Experimentally, ketamine may promote neuronal apoptotic lesions but, in usual clinical practice, it does not
induce neurotoxicity. The consequences of high doses, repeatedly administered, are not known. Cognitive
disturbances are frequent in chronic users of ketamine, as well as frontal white matter abnormalities (Mion,
2013).
11. Contributing to ketamine’s analgesic action is the inhibition of nitric oxide synthase resulting in a decrease in
nitric oxide production (Aroni, 2009). Ketamine also binds to opioid receptors but the binding affinity is too low
to contribute to analgesic effects (Rowland, 2005) although there are suggestions that the binding to sigma
opioid receptors may also play a role in its antidepressant activity (Robson, 2012).
12. Other actions, probably contributing to analgesic activity include blockade of voltage-sensitive calcium channels,
sodium channel depression and inhibition of monoamine reuptake (Quibell, 2011; Meller, 1996). Ketamine also
possesses anticholinergic activity (antagonist activity at muscarinic acetylcholine receptors) which may also
contribute to its psychotomimetic properties (Dunieu, 1995).
Taken from:
https://www.gov.uk/government/uploa...264677/ACMD_ketamine_report_dec13.pdf#page=12
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