Psych 181: Dr. AnagnostarasLec 11: PCP and HallucinogensPsych 181: Dr. AnagnostarasLec 11: PCP and Hallucinogens

PhencyclidinePhencyclidine

Dissociative anaestheticDissociative anaesthetic Parke Davis in 1950 (Serylan®)Parke Davis in 1950 (Serylan®) withdrawn from human use in 1965withdrawn from human use in 1965 related to ketamine (“K” Ketalar, Ketaset®)related to ketamine (“K” Ketalar, Ketaset®)

Illicit useIllicit use 1967 in San Francisco (PeaCe Pill)1967 in San Francisco (PeaCe Pill) Widespread in late 1970,’s, early 1980’sWidespread in late 1970,’s, early 1980’s (1980 - 22% of kids in grades 11-12 in N.Y.)(1980 - 22% of kids in grades 11-12 in N.Y.) Cheap, mostly distributed by the Crips nowadaysCheap, mostly distributed by the Crips nowadays

N

Phencyclidine (PCP)

Street namesStreet names

PCP, angel dust, crystal, horse tranquilizerPCP, angel dust, crystal, horse tranquilizer

““sherm” “embalming fluid” on cigarettes or sherm” “embalming fluid” on cigarettes or marijuanamarijuana

sold under many names and preparationssold under many names and preparations very often sold as ∆9-THC very often sold as ∆9-THC take orally, intranasal or i.v.; take orally, intranasal or i.v.;

or smokeor smoke

NH

O

Ketamine

CH3

Cl

EffectsEffects

Low dose (1-5 mg)Low dose (1-5 mg) alcohol-like effect (giddy drunken-like state, alcohol-like effect (giddy drunken-like state,

disinhibition)disinhibition)

Moderate dose (5-10 mg)Moderate dose (5-10 mg) distortion of space & time, psychotic distortion of space & time, psychotic

reactions (panic, agitation, depression, reactions (panic, agitation, depression, catatonia, paranoia)catatonia, paranoia)

““anaesthetic” and analgesic effectsanaesthetic” and analgesic effects blank stare, amnesia, mutismblank stare, amnesia, mutism

Toxic psychosisToxic psychosis

High dose (> 10 mg)High dose (> 10 mg) model of acute schizophrenia, including model of acute schizophrenia, including

true hallucinationstrue hallucinations (can last up to 1-7 days with high doses)(can last up to 1-7 days with high doses)

sometimes violent, abusive behaviorsometimes violent, abusive behavior

OverdoseOverdose Respiratory depression/seizuresRespiratory depression/seizures

Self-administrationSelf-administration

Reinforcing effectsReinforcing effects Readily self-administered in animalsReadily self-administered in animals

to point of intoxicationto point of intoxication modest tolerancemodest tolerance addiction and withdrawaladdiction and withdrawal

Mechanisms of actionMechanisms of action

Two distinct binding sitesTwo distinct binding sites Sigma siteSigma site

- generalizes with benzomorphans- generalizes with benzomorphans PCP site (“PCP receptor”)PCP site (“PCP receptor”)

PCP sitePCP site part of the NMDA glutamate receptorpart of the NMDA glutamate receptor

Glutamate (glutamic acid)Glutamate (glutamic acid)

Ubiqutious excitatory transmitterUbiqutious excitatory transmitter Depolarizes virtually all cellsDepolarizes virtually all cells

Primary transmitter for fast excitatory signallingPrimary transmitter for fast excitatory signalling

Glutamate receptorsGlutamate receptors

Ionotropic subtypesIonotropic subtypesNon-NDMA TypesNon-NDMA Types

AMPAAMPA KainateKainate

NMDANMDA Selectively binds N-Methyl-D-aspartateSelectively binds N-Methyl-D-aspartate

Metabotropic subtypesMetabotropic subtypes

Glutamate receptorsGlutamate receptors

Glutamate transporter

Glutamate Glutamate

Glutamate Glutamate

mGlu presynaptic autoreceptor

mGlu postsynaptic receptor

NMDA postsynaptic receptor

Na+,Ca2+

Na+,Ca2+

AMPA or kainate receptor

Na+

Na+10.2

PCP/NMDA interactionsPCP/NMDA interactions

Noncompetative antagonist at NMDA receptorNoncompetative antagonist at NMDA receptor site inside channel - blocks itsite inside channel - blocks it

not antagonizenot antagonizeAMPA/kainateAMPA/kainateeffectseffects

Extracellularside

Glutamate site

Cytoplasmicside

K+

Na+Ca2+

PCP site

10.10

Other actionsOther actions

Effects on many transmitter systemsEffects on many transmitter systems Action at sigma siteAction at sigma site Enhances DA releaseEnhances DA release

200

SalineD-Amphetamine

PCP Caffeine

600

1000

**

6-OHDAControl

Lo

com

oto

r a

cti

vit

y

17.20

NeuropathologyNeuropathology

Multiple vacuoles form in cytoplasm of some Multiple vacuoles form in cytoplasm of some neurons and mitochondria disappear 2-4 hrs neurons and mitochondria disappear 2-4 hrs after treatmentafter treatment Increasingly obvious 4-12 hrs after drugIncreasingly obvious 4-12 hrs after drug Disappear within 24 hrsDisappear within 24 hrs

Only certain parts of cortexOnly certain parts of cortex

Related to acute toxic psychosis?Related to acute toxic psychosis?

NeuropathologyNeuropathology

Eight day old rats treated once with PCP or MK-Eight day old rats treated once with PCP or MK-801 and brains examined 24 hours later.801 and brains examined 24 hours later.

_

+ Sustained activation ofNMDA receptors at crit-ical stages in develop-ment activates program-ed cell death.

See with PCP, ketamine(special K) and ethanol

Control Drug

PCP

Degeneratingneurons

ExcitotoxicityExcitotoxicity

GlutamateGlutamateexcitotoxicityexcitotoxicity

MK-801MK-801

VOCC

Depolarization Depolarization

Polyamines

NO

OH− free radical

AA

Polyamine site

NMDA receptor

Nerve terminal Glial

cellGlutamate

–AMPA kainate receptor

Na+Na+

Ca2+Ca2+

Mg2+

[K +]

ODC NOS PLA 2Proteases Endonucleases

Mitochondrial damage

Neuronal death 10.14

HallucinogensHallucinogens

Common featuresCommon features

HallucinogenHallucinogen the ability to evoke hallucinationsthe ability to evoke hallucinations

pseudohallucinations; illusions pseudohallucinations; illusions

PsychotomimeticPsychotomimetic ability to mimic endogenous psychosis ability to mimic endogenous psychosis

Phantasicum, PsychedelicPhantasicum, Psychedelic ““mind-expanding” change in perception of mind-expanding” change in perception of

realityreality

Major classesMajor classes

The LSD ‘Family’ The LSD ‘Family’ indole type hallucinogensindole type hallucinogens structural similarity to 5-HT (serotonin)structural similarity to 5-HT (serotonin) LSD (lysergic acid diethylamide)LSD (lysergic acid diethylamide)

N H

LSD-25

CH3N

C

O

NCH3CH2

CH3CH2

N

Indole

N H

CH2 NH2CH2’HO

Serotonin

Major classesMajor classes

The PhenylethylaminesThe Phenylethylamines structural similarity to CA’sstructural similarity to CA’s mixed hallucinogenic and stimulant effectsmixed hallucinogenic and stimulant effects mescalinemescaline

Dopamine

HO

HO

CH2 NH2CH2

HOR

HOCatechol

Mescaline

CH2 NH2CHCH3 O

CH3 O

CH3 O

LSD type hallucinogensLSD type hallucinogens

LSD (lysergic acid diethylamide)LSD (lysergic acid diethylamide) acid, blotters, windowpane, etc.acid, blotters, windowpane, etc.

N H

Lysergic acid

CH3

OH

N

C

O

LSD type hallucinogensLSD type hallucinogens

LSD (lysergic acid diethylamide, LSD-25)LSD (lysergic acid diethylamide, LSD-25) Hofman (1938)Hofman (1938)

• • led to Imitrex& Zomigled to Imitrex& Zomig

N H

LSD-25

CH3N

C

O

NCH3CH2

CH3CH2

N H

Lysergic acid

CH3

OH

N

C

O

LSD type hallucinogensLSD type hallucinogens

LSD (lysergic acid diethylamide)LSD (lysergic acid diethylamide) ergotergot

N H

Lysergic acid

CH3

OH

N

C

O

LSDLSD

Absorption and metabolismAbsorption and metabolism ToleranceTolerance

N H

LSD-25

CH3N

C

O

NCH3CH2

CH3CH2

LSD type hallucinogensLSD type hallucinogens

Psilocybin and PsilocinPsilocybin and Psilocin magic mushroommagic mushroom Psilocybe genusPsilocybe genus

N H

Psilocybin (N,N-Dimethyl-4-phosphoryltryptamine)

O

O

OH

PHO

CH2CH2 NCH3

CH3

N H

Psilocin (N,N-Dimethyl-4-hydroxytryptamine)

OH

CH2CH2 NCH3

CH3

LSD type hallucinogensLSD type hallucinogens

DMT (Dimethyltryptamine)DMT (Dimethyltryptamine) naturally-occuring LSD-like substance in naturally-occuring LSD-like substance in

plants; e.g. Piptadina peregrina (bean plant)plants; e.g. Piptadina peregrina (bean plant)

Morning Glory SeedsMorning Glory Seeds lysergic acid amide (LSA)lysergic acid amide (LSA)

Bufotenin (5-hydroxy-DMT)Bufotenin (5-hydroxy-DMT)

Harmine and HarmalineHarmine and Harmaline

The phenylethylaminesThe phenylethylamines

structural similarity to CA’sstructural similarity to CA’s mixed hallucinogenic and stimulant effectsmixed hallucinogenic and stimulant effects mescalinemescaline

Dopamine

HO

HO

CH2 NH2CH2

HOR

HOCatechol

Mescaline

CH2 NH2CHCH3 O

CH3 O

CH3 O

MescalineMescaline

in peyote cactus (Lophophora Williamsii)in peyote cactus (Lophophora Williamsii) mescal buttonmescal button

The phenylethylaminesThe phenylethylamines

MethoxyamphetaminesMethoxyamphetamines synthetic derivatives of mescalinesynthetic derivatives of mescaline many are so-called “designer drugs”many are so-called “designer drugs”

MethoxyamphetaminesMethoxyamphetaminesMethoxyamphetaminesMethoxyamphetamines

DOM (dimethoxymethylamphetamine)DOM (dimethoxymethylamphetamine) Called STP oftenCalled STP often

TMA (trimethoxyamphetamine)TMA (trimethoxyamphetamine) Similar to mescaline, but more potentSimilar to mescaline, but more potent

MDA and MDMAMDA and MDMA Methylenedioxyamphetamine and Methylenedioxyamphetamine and

methylenedioxymethamphetaminemethylenedioxymethamphetamine

Major effects (LSD)Major effects (LSD)

Sensory-PerceptualSensory-Perceptual pseudohallucinationspseudohallucinations illusionsillusions synesthesias, etc.synesthesias, etc.

Psychic ExperiencesPsychic Experiences

Somatic EffectsSomatic Effects

Adverse effectsAdverse effectsAdverse effectsAdverse effects

Bad ‘trips’Bad ‘trips’ FlashbacksFlashbacks

Mechanisms of actionMechanisms of action

Common action for hallucinogenic effects Common action for hallucinogenic effects sensory-perceptual effects and sensory-perceptual effects and psychedelic effectspsychedelic effects

Only short-term tolerance to LSD, no Only short-term tolerance to LSD, no withdrawal, dependence or addictionwithdrawal, dependence or addiction

LSD not lethal at very high dosesLSD not lethal at very high doses Cross tolerance for hallucinogenic effectCross tolerance for hallucinogenic effect Focus on 5-HT systems Focus on 5-HT systems

(structural similarity)(structural similarity)

Serotonin (5-hydroxytryptamine)Serotonin (5-hydroxytryptamine)

ReceptorsReceptors

5-HT 5-HT 1, 2…..1, 2…..

TryptophanTry H

5-HTPAADC

5-HT

5-HT

5-HIAA

MAO

Raphe

Synthesis &storage

Inactivation &degradation

9.1

(14 subtypesKnown)

Mechanisms of actionMechanisms of action

• • Initial prevailing view from Initial prevailing view from peripheral tissuesperipheral tissues

- block action of 5-HT (antagonist?)- block action of 5-HT (antagonist?)

• • Second view: agonist at inhibitory Second view: agonist at inhibitory autoreceptors autoreceptors

• • increases 5HT content and 5HIAA downincreases 5HT content and 5HIAA down

turnover down?turnover down?

• • inhibits firing of 5HT neuronsinhibits firing of 5HT neurons

• • discredited by presynaptic lesion studiesdiscredited by presynaptic lesion studies

Current Postsynaptic hypothesisCurrent Postsynaptic hypothesis

Binding to 5-HT receptors Binding to 5-HT receptors (over 14 subtypes)(over 14 subtypes)

LSD is fairly promiscuousLSD is fairly promiscuous(5-HT(5-HT1/2/5/6/7 1/2/5/6/7 types)types)

Mescaline not to 5-HTMescaline not to 5-HT1/5/7 1/5/7

All have affinity for 5-HTAll have affinity for 5-HT2 2 familyfamily 5-HT5-HT2A 2A shows greatest expression in neocortexshows greatest expression in neocortex

Hypothesis:Hypothesis: LSD and other hallucinogens are LSD and other hallucinogens are 5-HT5-HT2A2A postsynaptic receptor agonists postsynaptic receptor agonists