Psych 181: Dr. Anagnostaras Lec 6: Psychomotor stimulants

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Psych 181 Dr. AnagnostarasLec 6 Psychomotor
stimulants
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Psychomotor stimulants

• Large class of diverse compounds
• Stimulate alertness, arousal (psycho-)
• Stimulate motor activity (-motor)
• Major ones
• Amphetamines and related compounds
• Cocaine

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Amphetamines

• History and basic pharmacology
• ?-phenylethylamine derivatives
• sympathomimetic amines
• Naturally-occurring compounds
• cathinone
• ephedrine

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Naturally-occuring compounds

• Cathinone
• active agent in Khat (shrub)
• chewed
• synthetic version (meth-cathinone)

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Ephedrine

• from Ma Huang (herbal tea)
• isolated in 1920s
• bronchodilator for asthma
• pseudoephedrine is an isomer of ephedrine
• structure similar to epinephrine

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Neosynephrine

amphetamine
phenylalanine
ephedrine
pseudoephedrine
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Amphetamine

• History
• synthetic
• identified in search for substitute for ephedrine
  (Alles, 1927)
• structurally-related to catecholamines
• 1932, Benzedrine inhaler
• widespread adoption
• peak use in early 1970s (speed)
• new West Coast popularity ("tweakin")

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Forms of amphetamine

• Amphetamine (racemic)
• mixture of d- and l- isomers
• Benzedrine, Adderall
• bennies, speed
• d-Amphetamine
• dextroamphetamine
• Dexedrine
• dexies, hearts, speed

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Forms of amphetamine

• l-Amphetamine
• levoamphetamine
• less potent
• Methamphetamine
• dl-methylamphetamine
• Methedrine, Desoxyn
• meth, crystal, crank, speed
• most potent
• l-methamph "desoxyephedrine" (Vicks
  inhaler)

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Ice, Crank, Crystal Meth
US News World Report (1995)
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Ice, Crank, Crystal Meth

• Pure d-methylamphetamine HCl
• (can be smoked because of purity)
• Traditional synthesis
• amalgam method gt not very pure dl-methamphetamine
• 1981 main ingredient made illegal
• Synthesis from ephedrine
• pure d-methylamphetamine HCl

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Ice or Crystal
Smoked vs. OralAmphetamine
Blood level (ng/ml)
Hours
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Amphetamine-related drugs

• methylphenidate
• Ritalin
• attention deficit disorder
• fenfluramine
• Redux
• anorectic
• phenmetrazine
• Preludin
• anorectic
• subitramine
• Meridia
• anorectic

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Medical uses of amphetamine

• Obesity (anorexic effects)
• once major use - no longer
• Narcolepsy
• Attention deficit disorder

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Major effects - amphetamine

• Humans
• Autonomic functions
• increase blood pressure
• increase body temperature
• bronchodilation
• (sympathomimetic effects)

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Effects on CNS

• Analeptic (awakening)
• Anorexia
• Psychomotor stimulant effects
• decreased fatigue, increased alertness
• arousal
• elevated mood
• euphoria

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Effects non-human animals

• Autonomic effects
• same as humans
• Psychomotor stimulant effects
• complex dose-effect relations
• low doses - locomotor hyperactivity
• higher doses - stereotyped behavior
• Reinforcing effects
• self-administration and place preference

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Effects of repeated administration

• Tolerance
• most autonomic effects
• anorectic effects
• Sensitization
• psychomotor stimulant effects
• rewarding effects
• psychotomimetic effects (amphetamine psychosis)

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Sensitization

• Sensitization to the psychomotor stimulant
  effects of amphetamine
• Rats given 2.0 mg/kg of d-amphetamine once per
  day for 10 days
• Measure amount of drug-induced rotational
  behavior each day

Days
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Cocaine

• Source and history
• Naturally-occuring alkaloid in leaves of shrub
  Erythroxylon coca
• first reported use by Europeans - 1499
• active agent extracted in 1859 by Niemann
• widely used in late 1800s, early 1900s
• local anaesthetic effects - 1884
• procaine (1905)

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Cocaine - history of use
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Cocaine - history of use
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Forms of cocaine

• Raw leaves
• chew
• alkaloid content low (0.6 - 1.8 )
• not stable
• Coca paste
• initial extraction
• smoked
• around 80 cocaine

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Forms of cocaine

• Cocaine HCl
• purified converted to HCl salt
• crystalline form, water soluble
• pure if not diluted
• snorted or i.v.
• Cocaine free base
• extract (volatile solvents)
• smoked
• Crack
• free base made with baking
• soda ammonia
• crackles when heated

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Effects of cocaine

• Very similar to amphetamine (generalize in drug
  discrimination), but some major differences
• Duration of action
• Cardiovascular effects
• danger of CVA much higher
• Convulsive properties
• these sensitize
• Local anaesthetic effects
• Lidocaine, novacaine, benzocaine are related drugs

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Psychostimulant actions

• Mechanisms of action
• Primary actions on monoamine neurotransmission
• Monoamines
• (compounds with one amine group,- NH2)
• Epinephrine (E)
• Norepinephrine (NE)
• Dopamine (DA)
• Serotonin (5-HT)

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Psychostimulant actions

• Catecholamines (CA catecholaminergic)
• (compounds with catechol nucleus and amine)
• Epinephrine (adrenergic)
• Norepinephrine (noradrenergic)
• Dopamine (dopaminergic)
• Indolealkylamines (indole and amine)
• Serotonin (serotonergic)

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• CatecholamineSynthesis

8.1
8.3
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DAsynapse
8.1
Synthesis storage
MAOmonoamineoxidase
Inactivation degradation
Dopamine Metabolism
DA
COMT
MAO
DOPAC
3-MT
3-MT
HVA
MAO
Receptors
COMT
HVA
8.17
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NEsynapse
8.2
Synthesis storage
Inactivation degradation
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NEsynapse
8.2
Inactivation degradation
Receptors
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Distribution of NE
Locus coeruleus
8.30
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Distribution of NE
Locus coeruleus
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Distribution of DA
Nigrostriatal
Mesolimbic
8.19
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Serotonin (5-hydroxytryptamine)
Synthesis storage

• Receptors
• 5-HT 1-4

Inactivation degradation
Raphe
9.1
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Primary neurochemical effects

• Increase synaptic concentrations of monoamines
  (DA, NE, E 5-HT)

13.20
13.03
Coc
Increase in DA
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Primary site of action
8.13

• Monoamine transporter
• (both amphetamine and cocaine)
• actions on DA,NE 5-HTtransporters

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Actions of cocaine

• Cocaine and amphetamine have different actions
  on monoamine transporters
• Cocaine
• Blocks transporter
• prevents reuptake
• requires calcium

8.1
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Actions of cocaine
Human PET Scans

Normal
Cocaine
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Actions of cocaine

Time course of cocaine uptake into brain
-(11C)cocaine_
Fowler et al. (2001)
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Actions of cocaine

Time course to peak cocaine after i.v.
administration mirrors times course of subjective
effects
Fowler et al. (2001)
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Actions of cocaine

Fowler et al. (2001)
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Actions of amphetamine

• Release
• calcium independent
• not blocked by reserpine
• blocked by TH inhibition
• requires transporter(blocked by reuptake
  blockers)

8.1
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Locus of action

• Autonomic effects
• sympathetic nervous system
• Psychomotor and rewarding effects
• brain monoamine systems
• DA, NE and/or 5-HT?
• DA primary locus

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Role of DA

• Evidence that DA mediates the psychomotor
  stimulant and rewarding effects of
  psychostimulants
• Pharmacological studies
• Lesion studies
• Neurochemical studies
• Correlational studies
• Molecular biology studies

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Pharmacological studies
Amphetamine self-administration
Response rate ( control)
13.11
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Lesion studies

• 6-hydroxydopamine lesions

Control
Lesion
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Neurochemical studies

• Relationship between behavior and extracellular DA

Behavioral score
DA ( control)
13.9
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Correlational studies
Cocaine analogs
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Molecular biological studies

• The DA transporter knockout mouse

Normal
Knockout
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DA sub-systems

• Mesolimbic projections
• from VTA gt nucleus accumbens
• ventral striatum
• Nigrostriatal projections
• substantia nigra gt caudate-putamen
• dorsal striatum

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Nigrostriatal DA system

• Psychostimulant-inducedstereotyped behavior
• lesions
• local injections

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Mesolimbic DA system

• Locomotor hyperactivity and reward
• lesions
• local injections

Cocaine into N. Accumbens
Locomotor activity
13.19
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DA sub-systems

• Mesolimbic projections
• from VTA gt nucleus accumbens
• locomotor activity and reward
• Nigrostriatal projections
• substantia nigra gt caudate-putamen
• stereotyped motor patterns

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Amphetamine neurotoxicity

• Amphetamine and methamphetamineAre potentially
  neurotoxic
• requires high doses
• 10 to 50 times normal street dose(in rats
  primates may be more sensitive)
• high extracellular DA necessary

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d-Amphetamine

• Depletes DA
• Degeneration of DA terminals
• Primarily caudate (accumbens relatively spared)
• Cell bodies intact

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Methamphetamine

• Depletes DA and serotonin
• Degeneration of terminals
• Caudate DA and cortical and hippocampal 5-HT
• Cell bodies intact

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Baboons (humans?)
from Villemagne et al., J. Neurosci. (1998)
PET
PET
Binding
1 inj/2hr X 4 - 2-3 wks off
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Amphetamine neurotoxicity

• Does methamphetamine cause degeneration of
  striatal dopamine terminals in amphetamine
  addicts?

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Humans
from McCann et al., J. Neurosci. (1998)
PET images from control subjects, Parkinsons
patients, and abstinent methamphetamine and
methcathinone users (average period of
abstinence, 3 years)WIN-35,429 binding to DA
transporter
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DAT vs. VMAT

• Does methamphetamine cause degeneration of
  striatal dopamine terminals in amphetamine
  addicts?
• The controversy
• The DAT vs. VMAT as markers of dopamine terminal
  density

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DAT vs. VMAT
Vesicularmonoamine transporter
Dopamine transporter
13.4
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DAT vs. VMAT

• The controversy
• The DAT vs. VMAT as markers of dopamine terminal
  density
• The DAT is highly regulated, the VMAT is not.
  Therefore, the VMAT and not the DAT provides a
  reliable indicator of DA terminal density

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Wilson et al. (1996)

• Brain tissue from addicts show no change in VMAT
  binding, although is decrease in DAT
• Suggest is no neurotoxicity in amphetamine
  addicts

Wilson et al., Striatal dopamine nerve terminal
markers in human, chronic methamphetamine
users.Nature Medicine (1996)
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Methylenedioxymethamphetamine
"Ecstasy"
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Methylenedioxymethamphetamine

• MDMA (extacy, E, X, XTC,Adam) and MDA
• Synthesized in 1912, 1913 patent (Merck)
• anorectic in 1961
• not used clinically
• Dr. Shulgin
• Street use
• early 1980s popular at raves
• also adjunct to psychotherapy (clin trials 1993)
• illegal since 1985 (1st Schedule I by DEA)

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Several analogues
DOM - dimethoxyamphetamine - SF designer drug
(late '60s) - "STP" (Serenity Transquility
Peace) DOB - 4-bromo-2,5-dimethoxyamphetamine MD
A - 3,4-methylenedioxyamphetamine MDMA -
3,4-methylenedioxymethamphetamine 2-CB -
4-bromo-2,5,-dimethoxyhenethylamine
(NEXUS) (hallucinogen similar to LSD)
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Synthesis
Safrole is distilled from sassafras or nutmeg
oil (gt1000 doses 1 kg of safrole)
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MDMA

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Effects on behavior and affect

• Low doses
• relaxation, serenity, emotional closeness
• Moderate doses
• mild hallucinogenic effects
• intensification of feelings
• notorious memory impairment
• High doses
• amphetamine-like effects
• hyperthermia (heat stroke)
• hangover

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Distribution

• Typical use is in pill form
• "love" "hug" "club" drug
• permasmile
• mostly recreational
• 60-120 mg per pill
• LD50 50 mg/kg
• (3000 mg)
• take 1-2 pills
• 20-30 per pill (whl5)

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Different class than traditional drug users

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Effects on behavior and affect

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Can't recognize content from pill
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What is PMA?

• paramethoxyamphetamine
• "Death" "Mitsubishi Double Stack"
• "Killer" "Red Mitsubishi"
• substitute for MDMA
• cheaper to make
• slower longer effects
• more hallucinogenic
• incidence of toxic side effects much higher than
  MDMA (narrow safety margin)

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Effects on behavior and affect

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MDMA on the rise
1997 400,000 tablets seized 1999 3.3 million
tablets seized 2000 9 million tablets
seized During a period of time when
enforcement is very low. 2001 dealers can
unload gt100,000 tablets per week in major cities
1 in 4 teens in NYC say have tried.
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Neurochemical effects

• Monoamine neurotransmission
• increase synaptic DA and 5-HT
• blocks 5-HT transporter
• enters neuron and causes Calcium-independent
  release of 5-HT
• Neurotoxic effects
• potent neurotoxin
• 1-2 times street dose
• depletes forebrain 5-HT (not DA)

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MDMA MDA neurotoxicity

• Degeneration of 5-HT terminals
• fine axons from dorsal raphe
• beaded axons from median raphe spared
• can get 30 loss with single injection
• up to 80 with repeated injections
• Species differences
• primates more sensitive
• some evidence in humans (CSF 5-HIAA down)

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MDMA Neurotoxicity

Fischer, C. Hatzidimitriou, G. Wlos, J. Katz,
J. and Ricaurte, G. Reorganization of ascending
5-HT axon projections in animals previously
exposed to recreational drug 3,4-methelenedioxymet
ham-phetamine (MDMA, "Ecstasy"). Journal of
Neuroscience 155476-5485, 1995.
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MDMA MDA neurotoxicity
5-HT immunoreactive fibers in rat parietal cortex
MDA
PCA
Normal
9.9
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Squirrel monkeys 18 mo post- trtmt
Control
5-HT immuno- reactivity
Caudate
Hippocampus
Neocortex
MDMA
McCann et al. (1997)
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PET image from 1 control and one MDMA user
McN-5652, to label the 5-HT transporter
Normal
McCann et al., Lancet, 352(1998)1433.
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Cereberal Blood Flow
L. Chang et al. Psychiatry Research
Neuroimaging, Section 98, pp. 15-28, 2000.
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Amphetamine neurotoxicity

• d-Amphetamine
• DA only
• Methamphetamine
• DA and 5-HT
• Methylenedioxymethamphetamine (and MDA)
• 5-HT only