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Dissociative Anesthetics (Dextromethorphan (in cough syrup, DMX/robo,…
Dissociative Anesthetics
Phenylcyclidine
History
Tested as IV anesthetic agent in 1950s
Trance like catatonic state
vacant expression, fixed/staring gaze, waxy flexibility or rigidity
looked like catatonic schizophrenia
hallucinations, agitation, violence
terminated clinical trials
recreational use started in late 1960s
Ketamine
History
Tested as anesthetic agent in 1960s
less potent/shorter acting than PCP
not as bad neg side effects
used as anesthetic in children and veterinaries
much of elicit ketamine stolen from vets
General
Manufactured as liquid then evaporated to powder and can be put into pill form
Can sprinkle powder onto cigarettes/joints
Experience
Still conscious and aware but diff kind of consciousness
may feel pain but dont care
altered perceptions, loss of time sense
feeling of floating/leaving body
sudden insights/being one with the universe
produces dose-dependent increase in psychotic like symptoms
makes think maybe PCP and ketamine in NS are producing something similar to endogenous mental disorders i.e. schizophrenia
Dextromethorphan
in cough syrup
DMX/robo
medicinal dose 1/6-1/3 oz
recreational dose 2-10 oz
How they work
NONCOMPETITIVE antagonists at glutamate NMDA receptors
Glutamate
an amino acid
synthesized from glutamine by enzyme glutaminase
several functions in body
used in protein production
most common excitatory NT
glutamate and glutamine cycle between neurons and astrocytes
neurons
have glutamine transporters that uptake glutamine
glutaminase turns it to glutamate
glutamate leaves and is either recepted by postsynaptic cell or goes to EAAT3 on neuron where it is put into vesicles
also can go into EAAT1 &2 on astrocyte where glutamine synthase turns it into glutamine
astrocytes
have EAAT1 & 2 receptors that uptake glutamate and turn to glutamine via glutamine synthase
has glutamine transporters to eject glutamine from cell to neuron
EAAT = excitatory amino acid transporter
VGLUT = vesicular glutamate transporter
in neurons puts glutamate into vesicles
also a precursor to GABA
Glutamate goes to GABA by enzyme glutamic acid decarboxylase
GABA leaves cell and can get accepted by receptors on postsynaptic cell OR
Go to GAT 1 transporter on neuron
in neuron can get packaged into vesicles by GAT (vesicular GABA transporter)
or in neuron can be converted back to glutamate by GABA-T (GABA amino transferase)
or go to GAT 1,2 , or 3 transporter on astrocytes
Here GABA converted to glutamate which is then converted to glutamine by glutamine synthetase
would be totally messed up w/o glial cells
mechanism for clearing: can be taken up by high affinity transporters on the nerve terminal
allows Na+ to move inside the cell
blocks receptor at site other than the glutamate binding site
its actually below the Mg2+ block where PCP and ketamine would bind so to get in they need Mg2+ to be gone
is an excitotoxin
reason why its good to have 2 glut sinks because dont want too much in synapse
causes massive excitation
MSG is basically glutamate
glial cells come to fill space from cell damage and produces scarring
role of astrocytes
there are also excitatory transporters here
have both GAT (GABA transporters) and EATT (glutamate transporters/excitatory amino acid transporters)
clearance of glut from extracellular space
conserving a product that can be recycled over and over
may help compartmentalize glut needed for signaling
Glutamate Receptors
Metabotropic
8 subtypes mGluR1-8
Ionotropic
3 of them named after the selective agonists
amino-propanoic acid (AMPA)
kainate or kainic acid
N-methyl-D-aspartate (NMDA)
also allows Ca2+ flow into cell
2 different neurotransmitters are required to activate
Glycine/D-Serine are co-agonists with glutamate at NMDA receptors
co-agonist also has to be occupying protein but almost always is
glycine/D-serine site is target for modifying glut activity in a diff way
cant directly modify glut because 1) exitotoxic and 2) cant eliminate b/c involved in so many things
has Mg2+ binding site in channel that is occupied when resting membrane potential; blocks channel
If AMPA gets excited and creates membrane depolarization then the Mg2+ will leave and channel will be open
So to get to open need 1) mech for depolarizing membrane adj. to protein 2) occupancy of glut 3) occupancy of glycine/D-serine all for Mg2+ to leave and channel to open
Coincidence detector
if glut is bound but insufficient membrane depolarization it will stay blocked by Mg2+
if glut bound and membrane depolarized , Mg2+ block released and channel open to allow Na+ and Ca2+ in
All ionotropic glutamate receptor channels conduct Na+ ions into the cell
NMDA also allows CA2+ in