Dissociative Anesthetics

Phenylcyclidine

Ketamine

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

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

astrocytes

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

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

or go to GAT 1,2 , or 3 transporter on astrocytes

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)

Here GABA converted to glutamate which is then converted to glutamine by glutamine synthetase

is an excitotoxin

allows Na+ to move inside the cell

would be totally messed up w/o glial cells

mechanism for clearing: can be taken up by high affinity transporters on the nerve terminal

role of astrocytes

there are also excitatory transporters here

clearance of glut from extracellular space

conserving a product that can be recycled over and over

have both GAT (GABA transporters) and EATT (glutamate transporters/excitatory amino acid transporters)

reason why its good to have 2 glut sinks because dont want too much in synapse

may help compartmentalize glut needed for signaling

causes massive excitation

MSG is basically glutamate

glial cells come to fill space from cell damage and produces scarring

Glutamate Receptors

Metabotropic

Ionotropic

8 subtypes mGluR1-8

3 of them named after the selective agonists

amino-propanoic acid (AMPA)

kainate or kainic acid

N-methyl-D-aspartate (NMDA)

All ionotropic glutamate receptor channels conduct Na+ ions into the cell

NMDA also allows CA2+ in

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

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