• Psychomotor stimulants
– Cocaine
– Amphetamines
– but also – nicotine and
caffeine
• Cocaine is a compound
found in the leaves of the
shrub Erythroxylon coca.
– Native to South America
• Local inhabitants
consume cocaine by
chewing leaves.
– going back 2000-5000
years
• Coca chewers often
combine the leaves
with lime or ash
– This promotes
absorption
• Late 1850s German
chemists had
isolated pure
cocaine
• Became immensely
popular over the
next 30 years
• Probably the most
famous advocate
was Sigmund Freud
• By 1885 Parke Davis & Co.
pharmaceuticals was
manufacturing 14 different
forms of cocaine
• 1886 John Pemberton
introduced Coca-Cola
• Cocaine containing tooth drops
were even given to infants
when teething
– Cocaine is a local anesthetic
• 1914 Harrison Narcotic Act
was the beginning of
restrictions on cocaine
– Over time more and more
restriction were put into place
• From the 1920s-1960s cocaine was limited among a
small group of artists, musicians, and other performers
• 1970s was the first wave of cocaine use increase –
snorting cocaine
• 1980s (second wave)
– crack cocaine
• About 2 million people reported being current users
(within the previous month)
• About 6 million within previous year
• 34 million (14% of population) used at least once during
lifetime
• Coca leaves contain about 0.6-1.8% cocaine
• Initial extraction of the leaves results in a paste
that is about 80% cocaine
• Then converted to cocaine HCL a crystallized
version
– Readily water soluble
• Can be taken orally
• Intranasally
• IV
• Cocaine HCL is vulnerable to heat so that ruled out smoking
– Can be converted back to cocaine freebase
• Old way
–
–
–
–
–
Dissolve cocaine HCL in water
Add alkaline solution (ammonia)
Extract cocaine with an organic solvent (ether)
Freebasing refers to smoking cocaine obtained this way
Ether is highly flammable
• Preparation and smoking is dangerous
• New way
– Mix dissolved cocaine HCL with baking soda
– Heat and then dry
– Chunks of cocaine known as crack
• Popping noise when smoked.
11.5 Crystals of crack cocaine
• The different routes of
administration yield somewhat
different levels of plasma
cocaine
• Smoked probably an
understimate
– 1-3 puffs of vapor heated in a
flask
• A few hours of coca leaf
chewing produces plasma
concentrations equivalent to a
modest dose taking
intranasally or orally
• Cocaine is fat soluble
– Passes readily through the blood-brain barrier
• When smoked the brain is exposed to a very large surge
in the brain that is not reflected in the peripheral venous
system
• Once absorbed into circulation cocaine is rapidly broken
down by enzymes in the bloodstream and liver
– Half life 0.5-1.5 hours
– Thus, subjective high is brief
• Smoking may produce only a 30 minute high
– The breakdown products can persist longer
• Benzoylecgonine and be detected in urine for a number of days
following the last dose in a heavy user
• Cocaine is often taken with depressant drugs to
take the edge off the extreme arousal produced
by cocaine alone
• Cocaine and alcohol when taken together
produce a unique metabolite called
cocaethylene
– Has biological activity similar to cocaine
– Has a longer half life
• The combination of cocaine and alcohol may
increase the toxic effects of cocaine on the heart
and other organs
• Cocaine interacts with several
neurotransmitter systems
• Blocks the reuptake of three monoamine
neurotransmitters
– Dopamine
– Norepinephrine
– Serotonin
• Binds to and blocks the transporter
• Cocaine does not affect all monoamine
transporters equally
• Has highest affinity for 5-HT transporter,
followed by DA transporter, and NE transporter
• Nevertheless, it is blockade of the DA
transporter that plays the biggest role in the
stimulating, reinforcing, and addictive properties
of cocaine
• Many drugs used to treat depression block the
5-HT and NE transporter
– Do not have strong arousing effects
– Do not have abuse potential
• At high concentrations cocaine inhibits
voltage-gated NA+ channels in nerve cell
axons
– Blocks conduction
– Produces local anesthesia
• Novocaine (procaine)
• Xylocaine (lidocaine)
– Developed from cocaine
Acute behavioral effects of cocaine
• Cocaine high (mild to moderate effects)
–
–
–
–
–
–
Feelings of exhilaration and euphoria
Sense of well being
Enhanced alertness
Heightened energy
Great self confidence
Smoking produces a “rush”
• Intense sense of great pleasure and power
– Increases sociability and talkativeness
– Heightened sexual interest
– Can increase aggression
Note – how the effects become more negative as dose and duration of use go up.
• Cocaine can cause psychosis at high enough doses (we’ll talk more
about this later).
• Cocaine affects the behaviors of other animals as well
• Lab mice and rats are activated by low doses of cocaine
– Locomotion
– Rearing
– Sniffing
• Higher doses are replaced by focused stereotypies
– Stereotypy to stimulants in rats and mice
•
•
•
•
Intense sniffing
Continuous head and limb movements
Licking
Biting
– Humans sometimes show stereotypy as well
• Repetitive picking and scratching
• All animals tested so far readily learn to self-administer
cocaine I.V.
• Monkeys have been trained to smoke cocaine freebase
• If cocaine is made freely available the animals health
deteriorates
– High mortality rates
– Points to the powerful reinforcing properties of the drug
• Animals trained to discriminate cocaine from vehicle
readily learn
– Learning generalizes to amphetamine
• Indicates the two drugs are similar
– Much less generalization to caffeine
• Indicates the two drugs are not as similar.
• Cocaine is considered a sympathomimetic drug
– Produces symptoms of sympathetic nervous system activation
•
•
•
•
Increased heart rate
Vasoconstriction
Hypertension
Hyperthermia
• At low doses these effects are usually not harmful.
• At high doses these effects can be fatal
– Seizures
– Heart failure
– Stroke
• Intracranial hemorrhage
11.8 Computerized tomographic (CT) scan of a thalamic hemorrhage in a crack cocaine smoker
DA plays a key role in the subjective and behavioral effects of Cocaine
• Dopamine plays a central role in the
behavioral response of animals to cocaine
and amphetamine
• Table 11.2
• Note in Table 11.2 (previous slide) that amphetamine but
not cocaine microinjected in the nucleus accumbens is
reinforcing (Goeders & Smith, 1983)
– Surprising finding
– Not known why
• Differences in how cocaine and amphetamine work at the synapse?
• Anesthetic effects of cocaine?
• Subsequent work points to different regions of nucleus
accumbens
• There is evidence that rats will Self administer in to the
NA shell rather than NA core (Rod-Henricks et al, 2002).
Knock out mice
• More recently the neurochemical mechanisms of
cocaine action have been studied in genetic
knock out mice
• Led to some confusing results
• May say more about the knock out model than
about the mechanism of cocaine
• Notice in the next slide that knockout mice for
the dopamine transporter, still self-administer
cocaine.
– FR 2 schedule
• This finding implies that the DAT is not the only mechanism of
reward.
– Could be true
• Also could be that knockout mice adapt to the lack of dopamine
transporter
• There is some evidence that serotonin blockade may play a greater
role in the reinforcing effects of cocaine in knockout mice
– Fluoxetine (Prozac; 5-HT reuptake inhibitor) doesn’t support selfadministration in wild-type mice
• Does in knock out mice
– Fluoxetine also was found to stimulate DA release in the mesolimbic
pathway
• in knock out mice; but not in wild type mice
• Adds to already high levels (because no DAT)
• Perhaps this mediates reward
Neural mechanisms of psychostimulants in humans
• Brain imaging studies show that once a certain
minimum level of DAT occupancy is achieved
(40-60%) the subject may experience a “high”
– Studied with PET scan
• [11C]d-threo-methylphenidate
– a radiotracer which binds rapidly to the DAT in vivo
• See how much cocaine (or methylphenidate) reduced
[11C]d-threo-methylphenidate binding
– Use methylphenidate, which also binds to DAT because it can
be used in participants that have not previously used cocaine
• The intensity of the high depends on two other
things besides drug occupancy of DAT
– 1) The rate at which the transporter occupancy occurs
• IV and smoking = quick occupancy
– More intense high
– 2) The baseline of DA activity
• If DA release is low
– blockade of DAT may not have that much of an effect
• If DA release is high
– blockade of DAT seems to have a much greater effect
– See next slide.
• May explain individual differences in the high that people feel
– Some subjects with 60% DAT occupancy failed to report a high
» Perhaps they have low baseline DA levels
The role of DA receptor subtypes in the effects of psychostimulants
• There are 5 different subtypes of DA receptors
– D1 and D5 (D1-like family)
– D2, D3, and D4 (D2-like family)
• Studies have shown that antagonism of D1-like
or D2-like families can reduce behavioral
activation and reinforcing properties of
psychostimulants
– Nonselective antagonists
• So we don’t know which member or members of the families
are actually controlling the effects
Genetic knockouts and cocaine
• Knockout mice lacking D1 receptors
– Are not activated by cocaine
– Won’t self-administer cocaine
• Though they will work for food and for opiates
– Caine et al. (2007)
» Also blocked self-administration of D2 agonists
• Knockout mice lacking D2 receptors
– Are activated by cocaine
– Do self administer cocaine
• What do the results on the previous slide
mean?
– D1 receptors may play a bigger role in the
activational and rewarding effects of cocaine
than do D2 receptors
– Perhaps D1 receptors play a permissive role
for Dopamine agonists (Caine et al.)
• This would explain why D2 agonists were not
effective in D1 knockout mice
D3 receptors?
• D3 receptor
antagonist (SB277011-A) blocks the
enhancement of brain
reward (ICSS) that
normally occurs
• Implicates the D3
receptor in rewarding
properties of cocaine
Cocaine abuse and the effects of chronic cocaine exposure
• People usually begin taking cocaine
intranasally
• Most who try cocaine do not continue to a
pattern of drug abuse
–
–
–
–
–
Some report anxiety response
Availability of drug may be limited
Cost may be too much
Social and legal consequences
Fear of addiction
• Approximately 10-15% of initial users
eventually become abusers
• Initial use may be reinforced by the powerful
rewarding aspects of the drug
• Social reinforcement may also play a role
– Friends enjoy newfound energy and enthusiasm
• Transition to smoking or IV is often a
significant event in drug history
– Much greater high
– Often develop cocaine binges
• Bouts of drug use lasting from hours to days
• Nothing is more important than maintaining the high
– 3-day freebasing binge could involve consuming as much
as 150 g of cocaine
Tolerance and Sensitization
• Psychostimulants cause tolerance, but they
often also cause sensitization.
– sensitization can occur after a few exposures
– can last for weeks or months
• Why sometimes tolerance and sometimes
sensitization?
– Not fully understood
– Pattern of drug use may play a role
• Chronic exposure (continuous infusion)
– more likely to elicit tolerance
• Acute exposures (once daily)
– more likely to elicit sensitization
• See following graphs
11.12 Chronic cocaine administration can produce tolerance or sensitization (Part 1)
11.12 Chronic cocaine administration can produce tolerance or sensitization (Part 2)
Sensitization
• Sensitization can increase in strength after the
last drug use (that is during withdrawal).
– Presumably due to ongoing neurochemical changes.
• In some cases researchers have observed acute
tolerance along with long-term sensitization.
– Bradberry (2000)
• Monkeys self administering cocaine over 6 month test period
• Measured DA levels in the striatum
• If the monkeys injected themselves twice during a session,
– the DA response to the second dose was reduced (acute
tolerance)
– However, the DA response to the first dose each session
gradually escalated over the 6 month period (long-term
sensitization).
• These acute tolerance and long-term
sensitization effects may help us understand
patterns of drug use in humans
– The long-term sensitization may underlie the
increased craving that users experience (like the
incentive sensitization model we discussed in Ch 8).
– Users also report that during a cocaine or
amphetamine binge, they need more drug later to
obtain the high they had at the beginning
• Thus, there may be a short-term tolerance that wears off prior
to the next binge.
• Sensitization can be divided into two phases
• Induction
– Establishment of sensitization
– NMDA receptors (glutamate) seem to be involved
• Remember tolerance to opiates?
• Expression
– Changes in reactivity of DA nerve terminals in the
nucleus accumbens seem to be involved
• A given dose of cocaine causes greater increases in synaptic
DA levels
Health Consequences of chronic cocaine use
• As we stated before a single high dose can
cause a stroke or seizure
• What about chronic use?
– Effects on the body
• Heart problems
–
–
–
–
Chest pains
Cardiac arrhythmias (irregular hear rate)
Cardiac myopathy (damaged heart muscles)
Myocardial infarction (heart attack)
• There can also be adverse effects on the lungs, GI system,
and kidneys.
• Snorting can lead to perforation of the nasal septum
Maternal Cocaine use
• Effects on fetus
– Not completely understood
– Some children turn out okay
– Others have attentional deficits
– Some show Cognitive deficits
– May increase prenatal mortality
• The old correlation causation issue
Chronic cocaine and the brain
• Check out Box 11.1 in your book for an in depth discussion.
• In general there is evidence that chronic cocaine use can alter DA
functioning in the brain
– Of course we already expected this from the animal work that showed
tolerance and sensitization effects
• There is also some evidence for decreased grey matter in brain
areas associated with cognitive functioning
– Prefrontal and temporal areas
• There is some evidence that there may be behavioral consequences
– Impaired verbal memory
– Impaired attention
– Impaired motor function
• But….keep in mind…we have the old correlation vs. causation issue
again.
Pharmacotherapy for cocaine?
• Are there drugs we can use to treat cocaine
abuse?
• Desipramine (tricyclic antidepressant)
–
–
–
–
Mainly inhibits NE uptake
Most widely used drug to treat cocaine addiction
Used in adjunct with traditional therapies
Used most often with those that have been diagnosed
as also having depression (comorbid).
– Used for those diagnosed with cocaine abuse more
than the more severe cocaine dependence.
• Researchers are working on developing drugs
that might reduce cocaine’s euphoric effects
• Partial agonists of the DA receptor especially D1
and D3 are gaining a lot of interest
– Would compete with DA for access to the receptor
– Would have lower efficacy
– Possibly blunt the effects of cocaine
• BP 897 a D3 receptor partial agonist reduces
cocaine-seeking in rats
– Is currently in clinical trials
Cocaine vaccine?
• Animals can be immunized against cocaine
– Create antibodies that attack the cocaine molecule
– Less cocaine will get to the brain
– Seems to work with animals (see following figures).
• Has been tried with humans, but the antibodies
gradually disappeared over time
11.14 Reduction in behavioral responses to cocaine in vaccinated (immunized) rats (Part 1)
11.14 Reduction in behavioral responses to cocaine in vaccinated (immunized) rats (Part 2)
Amphetamines
• Amphetamine is the parent compound of a family of
synthetic psychostimulants
• True amphetamine comes in 2 forms
– 1-amphetamine (Benzedrine)
– d-amphetamine or dextroamphetamine (dexedrine)
• Other members of amphetamine-like psychostimulants
–
–
–
–
Methamphetamine
3,4-methylenedioxymethamphetamine (MDMA)
3,4-methylenedioxyamphetamine (MDA)
3,4-metheylenedioxy-N-ethylamphetamine (MDE)
• As can be seen in the following slide all of these
compounds are structurally quite similar to dopamine
11.15 Amphetamine and related psychostimulants
History of Amphetamine
• Ephedrine and Cathinone
are naturally occurring
plant compounds that are
similar to amphetamine
– chemical structure
presented in previous slide
• Cathinone is primary
active ingredient in khat
(qat)
– Shrub native to East Africa
and Arabia
History of Amphetamine
• Ephedrine comes from the herb Ephedra
vulgaris.
– Ephedrine (Ephedra) is obtained from the dried
branches of this plant
• Chinese have used Ephedra for more than 5000
years as an herbal remedy
– Reduces appetite
– Heightened energy
• Been marketed as a weight loss product in
health food stores
– Was very popular
History of Amphetamine
• Side effects of ephedra
– Elevated blood pressure
– Increased risk for heart attack or stroke
• In 2003 Baltimore Orioles pitcher Steve Bechler
collapsed and died during spring training in
Florida
– Had been taking high doses of ephedra containing
supplement to control weight
– Coroner ruled ephedra as a likely contributor to his
death
– FDA banned the sale of ephedra containing
supplements in 2004.
History of Amphetamine
• Ephedra played a role in the initial development
of amphetamine
• Purified ephedrine was used to treat asthma in
1920s
– Pseudoephedrine is a modern decongestant
• Similar compound but with less side effects
– There was concern that demand may be greater than
supply of the plant
– Amphetamine was used as a synthetic substitute.
• Smith, Kline, & French pharmaceuticals created an
amphetamine-containing inhaler in 1932
• Effective treatment for nasal or bronchial congestion
History of Amphetamine
• Some patients began to overuse the inhalers
– Often available without prescription
• Contained a cotton plug which contained the
amphetamine
– Some folks began to open the inhalers and either chew or
swallow the cotton plug, or extract the amphetamine for injection.
• Amphetamine tablets were marketed in 1935 as a
treatment for narcolepsy.
– Amphetamines are still used for this purpose today.
• 1940s amphetamine was widely embraced by medical
profession
– American military personnel were given amphetamine to
maintain alertness and forestall sleep while on duty
History of Amphetamine
• After WWII there was a surge in street use
of amphetamine
– 1950s and 60s students used amphetamines
as study aids
• The peak of use occurred in early 70s
– Since then cocaine use has surpassed
amphetamine use
– An exception to this trend is the recent
upsurge in methamphetamine use
Amphetamine/Methamphetamine
• Amphetamine and Methamphetamine are quite
similar pharmacologically
• Amphetamine is typically taken PO, IV, or SC
– AKA: uppers, bennies, dexies, black beauties, diet
pills
• Methamphetamine is more potent than
amphetamine
– Typically taken PO, Intranasally, IV, or smoked.
– AKA: meth, speed, crank, zip, go
– Smoking can be done with a glass pipe, or by heating
on a piece of aluminum foil (“chasing the dragon”)
Crystal Meth/Ice
• Methamphetamine HCL
is a crystal form that is
particularly suitable for
smoking
– AKA ice or crystal meth
• Began showing up in
Hawaii in the 1980s.
• Now spread to many
parts of the country.
– Especially west, south, and
midwest
• Inexpensive to make and
highly addictive
Patterns of use
• Use of amphetamine/methamphetamine
often occurs in binges “speed freaks”
– Can last for days
• Little sleep or eating occurs during a run
– Check out “Spun”
• Metabolized by the liver at a slow rate
– Very long half-life, so the high from
amphetamine/methamphetamine lasts much
longer than that of cocaine
mechanism of action (a triple whammy)
• Amph./methamp. are indirect
agonists of the
catecholaminergic system
– Enter the terminal button (via
DAT) and cause release of
catecholamines from terminal
button
– 2 mechanisms involved
• 1) DA molecules are released
from synaptic vesicles into the
cytoplasm
• 2) the dopamine transporter
moves the DA out into the
synapse (reverse transport)
– This reverse transport
prevents reuptake.
– Very high doses can also
inhibit monoamine oxidase
Amphetamines do have therapeutic uses
• Used to treat narcolepsy
• Some forms are also used to treat ADHD
– Low doses of psychostimulants can cause a calming effect in
ADHD children
– Usually combined with counseling (therapy) of some sort
• Methylphenidate is available in several forms to treat
ADHD
– Ritalin (immediate release form)
• Works 3-4 hours
– Ritalin SR
• Lasts 6-8 hours
– Ritalin LA and Concerta
• Can last an entire day
• How can stimulants be calming?
– Human adults given low doses of methylphenidate are more
likely to show arousal and hyperactivity
– But young people appear to be calmed
• Some have speculated that this response is specific to
children with ADHD
• Other researchers have shown that even children that
don’t have ADHD have increased attention and lower
activity levels to therapeutic doses of amphetamine
– Leading to speculation that this response to amphetamine is a
general developmental phenomenon
• Apparently low doses can
reduce activity in young
rats as well.
– Kuczenski and segal
(2002) – graph
– Oral doses of
methylphenidate during
active part of cyle (night)
– Not shown in graph is that
high doses (5 mg/kg)
caused increased activity
High doses and chronic use of amphetamine
• Amphetamines can cause psychotic reactions
• Same sorts of symptoms that we discussed for
cocaine psychosis
• These kinds of effects usually require chronic
high doses in order to develop.
– After a few “speed runs”
• Perhaps may cause “flash backs”
– Triggered by stressful events
– Perhaps previous drug use caused heightened stress
sensitivity?
Amphetamine Neurotoxicity
• Animals exposed to multiple doses of
methamphetamine
– Long-lasting reductions in
• DA levels
• Tyrosine hydroxylase
– Remember key enzyme in DA synthesis
• Dopamine transporter
– Indicates damage to DA axons and terminals
• Histology experiments show degenerating axons
– Also causes damage to serotonergic axons
Amphetamine neurotoxicity in humans?
• PET scan data indicate large losses of DAT in the
striatum for previous methamphetamine users.
– Doesn’t necessarily mean loss of axons, but animal data would
imply that it might
• Notice the lack of DAT in parkinson’s patients (PD)
compared to control
– Then compare the slides for methamphetamine users
• Given that striatal DA activity occurs during normal
aging, if nothing else these findings might imply an
increased susceptibility to Parkinson’s disease
MDMA (Ecstasy)
• Developed by Merck pharmaceutical company in
1914
• Forgotten for decades, but reemerged in the
1970s
– Some psychotherapists began to give MDMA to
clients during therapy
• Caused clients to communicate better
• Open up their emotions, experience greater closeness and
empathy for others
– People began to use it recreationally
• AKA: Ecstasy, XTC, Adam
• 1985 the DEA made MDMA a schedule 1 drug
• Psychological effects of MDMA
– Produces mild euphoria
– Increased energy
– Enhanced sensory perception
– Feelings of well being and self-confidence
– Desire to interact with other people
• Physical effects of MDMA
–
–
–
–
–
–
–
–
Increased heart rate
Increased blood pressure
Elevated body temperature
Sweating
Salivation
Tremor
Tightening of jaw muscles
Teeth grinding
• MDMA was closely associated with Rave scene
– This led to concern about heatstroke and dehydration
• Could be fatal
Mechanism of action of MDMA
• Acts at DA and serotonin neurons
– Enhances release and blocks reuptake of
both NTs
• The primary mechanism of action appears
to be activation of the serotonergic
system.
– Probably explains the subjective and
physiological differences between MDMA and
amph./methamp.
MDMA toxicity?
• Animal studies
– Repeated high doses have been shown to
damage serotonergic pathways in the brain
• Decreased serotonin levels and pruning (loss of
terminal button branches) of serotonin axons in the
the cortex and hippocampus
– There is evidence of regrowth, but the
regrowth is not always normal
• Some show long lasting deficits (see next figure)
• Some studies have actually shown development of
excessive serotonergic input
•
•
•
Monkeys stained for serotonergic
neurons in neocortex
Control monkey – left column
Middle column
– 5 mg/kg MDMA twice daily for 4
days
• Sacrificed 2 weeks later
•
Right column
– 5 mg/kg MDMA twice daily for 4
days
• Sacrificed 7 years later
•
From what I can gather – (don’t
hold me to this).
– A pretty high dose for humans
• About 2.5 mg/kg
– Typical dose?
• About 1-1.5 mg/kg
• Does this sort of toxicity occur in humans?
– Critics say pretty high doses in animal studies
• Humans may not typically expose themselves to such levels
– However, there are signs of deficits in heavy users
•
•
•
•
Reduced 5-HIAA (principle metabolite) of serotonin
Decreased 5-HT transporter density
Some signs of cognitive deficits
Decreased performance on memory tests
– Again…..correlational (poly drug use; preexisting conditions)
– Also typically study people that are chronic heavy users of
MDMA
– Hard to say what the long-term effects of a few doses of MDMA
are.