Loading presentation...

Present Remotely

Send the link below via email or IM

Copy

Present to your audience

Start remote presentation

  • Invited audience members will follow you as you navigate and present
  • People invited to a presentation do not need a Prezi account
  • This link expires 10 minutes after you close the presentation
  • A maximum of 30 users can follow your presentation
  • Learn more about this feature in our knowledge base article

Do you really want to delete this prezi?

Neither you, nor the coeditors you shared it with will be able to recover it again.

DeleteCancel

Make your likes visible on Facebook?

Connect your Facebook account to Prezi and let your likes appear on your timeline.
You can change this under Settings & Account at any time.

No, thanks

Ketamine

No description
by

Thomas Luechtefeld

on 6 May 2014

Comments (0)

Please log in to add your comment.

Report abuse

Transcript of Ketamine

Ketamine
Public Health Role
Experimental Models
Brain Imaging
Behavioral/Cognitive Models
1990s
2000 - Today
1970s
1960s
Dance Scene
Problem
Steady recreational use increases
90,000 UK Ketamine users
Serious Bladder problems (cystitis [UTI])
2014 - UK reclassification to Class C
Death primarily due to accident
Therapy
2006 Yale & NIMH antidepressant study
2010- synaptogenesis
2011- reverse of dendrite atrophy
Emergency medicine
Ketamine is the preferred ER anesthetic for burn victims and patients with unknown medical history.
Also highly used for pediatric anesthesia
When was Ketamine discovered?
The Psychonauts
Recreational use of Ketamine starts to take off
Drug culture
"The Scientist" - John Lilly
"Journeys Into the Bright World" - Marcia Moore
Isolation Tanks
Spiritual and existential relationships
Regression therapy
Possible use as antidepressant
1962 PCP derivative Ketamine made.
1964 First Human use "Dissociative Anesthesia"
Use in the Vietnam war as an anesthetic
Patented for use as an animal anesthetic
http://mindprod.com/obitlilly.html
Sources
Ketamine Timeline: A new model of rapid acting antidepressant.
http://news.yale.edu/ketamine-timeline-new-model-rapid-acting-antidepressant
History of Ketamine. Dagostino, Tony.
http://www.tonydagostino.co.uk/history-of-ketamine.htm
Kalsi, Wood, Dargan. The epidemiology and patterns of acute and chronic toxicity associated with recreational ketamine use.
Autry, Adachi, Nosyreva. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011. PMID: 21677641
Referenced many sources from
http://en.wikipedia.org/wiki/Ketamine
Liu. Role of glycogen synthase kinase-3β in ketamine-induced developmental neuroapoptosis in rats. British Journal of Anesthesia 2013. PMID: 23533250
Li N. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010. PMID: 20724638
H Yamanaka. A possible mechanism of the nucleus accumbens and ventral pallidum 5-HT1B receptors underlying the antidepressant action of ketamine: a PET study with macaques. PMCID: PMC3905222
Olney. Pathological Changes Induced in Cerebrocortical Neurons by Phencyclidine and Related Drugs. 1989.PMID: 2660263
The Posterior Cingulate. 2010
http://www.beckleyfoundation.org/2010/10/the-posterior-cingulate/
Krystal. Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans
The epidemiology and patterns of acute and chronic toxicity associated with recreational ketamine use. 2011
The epidemiology and patterns of acute and chronic toxicity associated with recreational ketamine use. 2011
Humans Cognitive Tests
Behavioral Tests in Rats
19 subjects recruited via advertisement.

0.1-0.5mg/kg Ketamine or Ketamine hydroxycholride.

1. Wisconsin Card Sorting
2. Continuous performance
Vigilance
3. verbal fluency

Behaviors similar to schizophrenia observed. Perceptual alterations. Impairment on all cognition tests.

Ketamine is still the favored anesthetic for emergency patients with unknown medical histories
Neuroapoptosis
Depression in Rhesus Monkeys
AMPA Receptor Mediated Anti-Depressant Effect
http://flipper.diff.org/app/items/3779
Olney
Posterior cingulate vacuolar bodies

“Before engaging in speculation, it must be acknowledged that rodent data provide an imprecise basis at best, and an irrelevant basis at worst, for evaluating human risk.”

Neurons of the Posterior Cingulate
http://www.beckleyfoundation.org/2010/10/the-posterior-cingulate/
Direct contributions to
Depression
Decision making
Decline linked to Alzheimers
Glycogen Synthase Kinase 3 Beta
Zou. Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain
Monkey Ketamine Induced Neuroapoptosis
Ketamine dephosphorylates GSK, resulting in extrinsic apoptosis in rats.
A potential pathway for Ketamine proposed in 2013.

GSK-3B has numerous downstream effects and ketamine is associated with a temporal decrease in its phosphorylation.

Methods used include:
Flash freeze
Fluoro-Jade C for neuron degradation
Caspase-3 immunostain
western-blotting
and more.

GSK-3B overactivity associated with Alzheimer's. NMDAR antagonists already used for alzheimer's treatment.
Role of glycogen synthase kinase-3β in ketamine-induced developmental neuroapoptosis in rats. 2013.
Dobbing and Sands72 brain growth spurt hypothesis (human age in months, rat age in days)
Single exposures of Ketamine:
reported to have long lasting anti-depressant effects.
helping depression victims unresponsive to traditional medication.

The NMDAr antagonist property of ketamine mediates short term anti-depressive effects.

It also mediates the acute effects of ketamine use.

Acute effects:
delirium
aphasia
hallucinations
etc.

NMDAr involved in memory, synaptic plasticity,
learning.
1. Ketamine blocks NMDAR

2. Excess glutamate can build up (short term).

3. AMPA receptor is activated by remaining glutamate.

AMPA receptor highly involved in
long term potentiation.

Questionable whether this effects persists in NMDAR antagonized conditions.
Large scale apoptosis could mediate chronic effects of ketamine use.

Chronic effects:
depression
impaired memory
impaired verbal skills

However long-term infrequent users suffer from none of these effects.
Synaptogenesis
PET Imaging of Rhesus Monkeys
What is NBQX?
Antagonist of the AMPA receptor
Shown to remove antidepressant effects of ketamine.

PET imaging shows ketamine:
Increases 5-HT1B serotonin receptor
Decreases serotonin transporter
prevents serotonin reuptake

PET imaging shows NBQX
Completely blocks ketamine mediated serotonin increases.

"Effect of ketamine on the 5-HT1B AMPA receptor activation, likely contributes to antidepressant action."
Voxel-wise comparisons of [11C]AZ10419369 BPND between the ketamine-treated and untreated conditions. Coronal views of the clusters of significant increases in the ketamine-treated condition are shown. Coronal sections are shown in the level of Acb (a) and GP (b). The statistical threshold was set at P<0.001 uncorrected (T-value >4.3). Acb, nucleus accumbens; Cau, caudate nucleus; GP, globus pallidus; Put, putamen.
a1 = control b1 = ketamine b2= superposition
Source
Yamanaka. A possible mechanism of the nucleus accumbens and ventral pallidum 5-HT1B receptors underlying the antidepressant action of ketamine: a PET study with macaques. 2014.
source

Olney.Pathological Changes Induced in Cerebrocortical
Neurons by Phencyclidine and Related Drugs . 1989

Liu.Role of glycogen synthase kinase-3β in ketamine-induced developmental neuroapoptosis in rats. 2013.
source
Krystal. Subanesthetic Effects of the Noncompetitive
NMDA Antagonist, Ketamine, in Humans
Psychotomimetic, Perceptual, Cognitive, and Neuroendocrine Responses. 1994
users match cards without
knowing the rules.
Seek a fast acting anti-depressant.
Test Ketamine in mice via:
Forced Swim Test
Novelty suppressed Feeding
Learned Helplessness

Source
Autry. NMDA receptor blockade at rest triggers rapid
behavioural antidepressant responses. Nature 2011
Forced Swim Test
a. ketamine
b. CPP Midafotel
c. MK-801 Dizocilpine
All Non-Competitive NMAR antagonists
Anita. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011
ketamine efficacious
in chronic depression mice

conventional anti-depres.
require multiple doses
and long term use.

What is BDNF?
Brain derived neurotrophic factor
hippocampal increase
infusion causes sustained anti-dep.
ketamine ineffective in BDNF knockouts.
excitotoxicity
from EAAT
loss
1. Mice are taped so they cannot easily escape.
2. Shocks are applied to mouse feet.
3. Eventually mouse becomes frightened and
withdrawn.

Mice may develop PTSD symptoms.

Mice create a good model for depression.

After repeated trials mouse stops trying to escape.
Animal Model of Depression. http://psylab.idv.tw/Animal%20models%20of%20depression-detail.htm
Learned Helplessness
Measure time until mouse feeding in novel environments.

Measure amount mouse eats.

Anxious mice are less likely to feed in novel environments.
Animal Model of Depression. http://psylab.idv.tw/Animal%20models%20of%20depression-detail.htm
Novelty Suppressed Feeding
http://www.psychogenics.com/oveltyfeeding.html
Source
Li et al. mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists. Science 2010.
Ketamine actiates mTor pathway (rapamyacin target).
Low dose of ketamine used in clinical trials

Prefontal cortex mTor activation
planning
complex cognitive behavior
personality
ARC
actin formation in cellular cortex
fear, spatial mem.
Synapsin
regulate # of neurotrans vesicles
k/os can't learn
GluR1
subunit for glutamate receptors
PSD95
Anchors synaptic proteins.
Including NMDA receptors
BDNF Translation not Transcription
RT-PCR BDNF shows no increase with ketamine
But there is more BDNF. Translation not transcription.

This means that the mTor pathway (another activated pathway) is probably not involved in direct antidepressant effects.

Instead EEF2 Kinase effects BDNF translation.
Full transcript