Transcript Phencyclidine - University of California, San Diego

Psych 181: Dr. Anagnostaras
Lec 11: PCP and Hallucinogens
Phencyclidine
N
Dissociative anaesthetic



Phencyclidine (PCP)
Parke Davis in 1950 (Serylan®)
withdrawn from human use in 1965
related to ketamine (“K” Ketalar, Ketaset®)
Illicit use




1967 in San Francisco (PeaCe Pill)
Widespread in late 1970,’s, early 1980’s
(1980 - 22% of kids in grades 11-12 in N.Y.)
Cheap, mostly distributed by the Crips nowadays
Street names




PCP, angel dust, crystal, horse tranquilizer
“sherm” “embalming fluid” on cigarettes or
marijuana
sold under many names and preparations
O
very often sold as ∆9-THC
NH CH3
take orally, intranasal or i.v.;
or smoke
Cl
Ketamine
Effects
Low dose (1-5 mg)

alcohol-like effect (giddy drunken-like state,
disinhibition)
Moderate dose (5-10 mg)
distortion of space & time, psychotic
reactions (panic, agitation, depression,
catatonia, paranoia)
 “anaesthetic” and analgesic effects
 blank stare, amnesia, mutism

Toxic psychosis
High dose (> 10 mg)
model of acute schizophrenia, including
true hallucinations
 (can last up to 1-7 days with high doses)
 sometimes violent, abusive behavior

Overdose

Respiratory depression/seizures
Self-administration
Reinforcing effects

Readily self-administered in animals
 to point of intoxication
 modest tolerance
 addiction and withdrawal
Mechanisms of action
Two distinct binding sites
Sigma site
- generalizes with benzomorphans
 PCP site (“PCP receptor”)

PCP site
 part
of the NMDA glutamate receptor
Glutamate (glutamic acid)
Ubiqutious excitatory transmitter

Depolarizes virtually all cells

Primary transmitter for fast excitatory signalling
Glutamate receptors
Ionotropic subtypes
Non-NDMA Types
 AMPA
 Kainate
NMDA
 Selectively binds N-Methyl-D-aspartate
Metabotropic subtypes
Glutamate receptors
m Glu
Glutam ate
Glutam ate pre s ynaptic
autore ce ptor
Glutam ate
trans porte r
Glutam ate
m Glu
pos ts ynaptic
re ce ptor
10.2
Glutam ate
AM PA or
Na+ k ainate
re ce ptor
Na+,
Ca2+
Na+
Na+,
Ca2+
NM DA
pos ts ynaptic
re ce ptor
PCP/NMDA interactions
Noncompetative antagonist at NMDA receptor
 site inside channel - blocks it
K+
Glutamate site

not antagonize
AMPA/kainate
effects
Extracellular
side
Cytoplasmic
PCP site
side
10.10
Na+
Ca2+
Other actions
Effects on many transmitter systems

Action at sigma site
Enhances DA release
Control
6-OHDA
Locomotor activity

1000
600
*
*
200
17.20
PCP
Saline
D-Am phe tam ine
Caffe ine
Neuropathology

Multiple vacuoles form in cytoplasm of some
neurons and mitochondria disappear 2-4 hrs
after treatment
 Increasingly obvious 4-12 hrs after drug
 Disappear within 24 hrs
Only certain parts of cortex

Related to acute toxic psychosis?

Neuropathology
Eight day old rats treated once with PCP or MK801 and brains examined 24 hours later.
+
_
Sustained activation of
NMDA receptors at critical stages in development activates programed cell death.
See with PCP, ketamine
(special K) and ethanol
Control
Drug
Degenerating
neurons
PCP
Excitotoxicity
Nerve
terminal
Glial
cell
Glutamate
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
Glutamate
excitotoxicity
MK-801
[K ]
NMDA
receptor
Polyamine
site
AMPA–
kainate
receptor
VOCC
Mg 2
Depolarization
Na 
Ca 2
ODC
Polyamines
NOS
PLA 2
NO
AA
Depolarization
Na 
Ca 2
Proteases
Endonucleases
Mitochondrial
damage
OH free radical
Neuronal
death
10.14
Hallucinogens
Common features
Hallucinogen

the ability to evoke hallucinations
pseudohallucinations; illusions
Psychotomimetic

ability to mimic endogenous psychosis
Phantasicum, Psychedelic

“mind-expanding” change in perception of
reality
Major classes
The LSD ‘Family’
indole type hallucinogens
 structural similarity to 5-HT (serotonin)
O
 LSD (lysergic acid diethylamide)
C

HO
N
Indole
CH 2 CH 2’ NH 2
N
CH2
CH2
N
CH3
CH3
CH3
N
H
Serotonin
N
H
LSD-25
Major classes
The Phenylethylamines
structural similarity to CA’s
 mixed hallucinogenic and stimulant effects
HO
 mescaline

HO
CH3
HO
CH2
CH2
NH2
CH3
O
CH2
HO
Dopamine
Catechol
O
CH3
O
Mescaline
CH
NH2
R
LSD type hallucinogens
LSD (lysergic acid diethylamide)
acid, blotters, windowpane, etc.

O
C
OH
N
CH3
N
H
Lysergic acid
LSD type hallucinogens
LSD (lysergic acid diethylamide, LSD-25)
 Hofman (1938)
• led to Imitrex& Zomig
O
C
N
CH2
CH2
N
CH3
CH3
CH3
N
H
LSD-25
O
C
OH
N
CH3
N
H
Lysergic acid
LSD type hallucinogens
LSD (lysergic acid diethylamide)
ergot

O
C
OH
N
CH3
N
H
Lysergic acid
LSD
Absorption and metabolism
 Tolerance

O
C
N
CH2
CH2
N
CH3
CH3
CH3
N
H
LSD-25
LSD type hallucinogens
Psilocybin and Psilocin
magic mushroom
 Psilocybe genus

OH
HO
P
O
O
CH2
CH2
N
CH3
CH3
N
H
Psilocybin
(N,N-Dimethyl-4-phosphoryltryptamine)
OH
CH2
CH2
N
CH3
CH3
N
H
Psilocin
(N,N-Dimethyl-4-hydroxytryptamine)
LSD type hallucinogens
DMT (Dimethyltryptamine)

naturally-occuring LSD-like substance in
plants; e.g. Piptadina peregrina (bean plant)
Morning Glory Seeds

lysergic acid amide (LSA)
Bufotenin (5-hydroxy-DMT)
Harmine and Harmaline
The phenylethylamines
structural similarity to CA’s
 mixed hallucinogenic and stimulant effects
 mescaline

HO
R
HO
CH3
HO
CH2
CH2
NH2
CH3
O
CH2
HO
Dopamine
Catechol
O
CH3
O
Mescaline
CH
NH2
Mescaline
in peyote cactus (Lophophora Williamsii)
 mescal button

The phenylethylamines
Methoxyamphetamines
 synthetic
derivatives of mescaline
 many are so-called “designer drugs”
Methoxyamphetamines
DOM (dimethoxymethylamphetamine)

Called STP often
TMA (trimethoxyamphetamine)

Similar to mescaline, but more potent
MDA and MDMA

Methylenedioxyamphetamine and
methylenedioxymethamphetamine
Major effects (LSD)
Sensory-Perceptual
pseudohallucinations
 illusions
 synesthesias, etc.

Psychic Experiences
Somatic Effects
Adverse effects
Bad ‘trips’
 Flashbacks

Mechanisms of action
Common action for hallucinogenic
effects sensory-perceptual effects and
psychedelic effects
 Only short-term tolerance to LSD, no
withdrawal, dependence or addiction
 LSD not lethal at very high doses
 Cross tolerance for hallucinogenic effect
 Focus on 5-HT systems
(structural similarity)

Serotonin (5-hydroxytryptamine)
Receptors
5-HT 1, 2…..
Synthesis &
storage
5-HT
MAO
5-HIAA
(14 subtypes
Known)
Inactivation &
degradation
Tryptophan
5-HTP
5-HT
AADC
Try H
Raphe
9.1
Mechanisms of action
• Initial prevailing view from peripheral tissues
- block action of 5-HT (antagonist?)
• Second view: agonist at inhibitory
autoreceptors
• increases 5HT content and 5HIAA down
turnover down?
• inhibits firing of 5HT neurons
• discredited by presynaptic lesion studies
Current Postsynaptic hypothesis
Binding to 5-HT receptors (over 14 subtypes)

LSD is fairly promiscuous
(5-HT1/2/5/6/7 types)

Mescaline not to 5-HT1/5/7
All have affinity for 5-HT2 family
5-HT2A shows greatest expression in neocortex
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Hypothesis: LSD and other hallucinogens are
5-HT2A postsynaptic receptor agonists