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Cocaine and Amphetamines
Introductory article
Article Contents
George V Rebec, Indiana University, Bloomington, Indiana, USA
. Ephedrine, the First General Stimulant
As stimulants, cocaine and amphetamines heighten arousal and increase behavioural
activation. More ominously, rapid delivery of a high concentration of these drugs to the
brain triggers a state of euphoria (the so-called ‘flash’ or ‘rush’) that creates an alarming
potential for abuse. Cocaine and amphetamines are phenylisopropylamines whose
stimulant properties have been known for centuries.
. General Stimulants and an Increase in the Availability
of Norepinephrine (Noradrenaline)
. Sympathomimetics as General Stimulants
. Stimulation of Behavioural Arousal and Vigilance
. Stimulation of Pleasure
. Overdoses and Acute Psychosis
. Use as Therapeutic Agents
. Caffeine and Other Xanthines
. Summary
Ephedrine, the First General Stimulant
The stimulant effects of ephedrine, an alkaloid of the
shrub, Ephedra vulgaris, were described in China more
than 5000 years ago. Local physicians typically used the
plant, also known as ma huang, as a herbal remedy for
asthmatic wheezing and other pulmonary problems. These
disorders are caused by severe constriction of the bronchial
tree, and ephedrine simply relaxes bronchial muscle to
improve respiration. Although Western medicine relied on
intravenous epinephrine (adrenaline) to treat severe
asthma, pharmaceutical firms recognized the value of
developing an oral medication for bronchial congestion.
By 1935, several ephedrine analogues were synthesized,
some of which remain in use as nasal decongestants (e.g.
pseudoephedrine). The amphetamines were developed as
part of this effort. In fact, the first synthetic ephedrine
analogue was a mixture of d- and l-amphetamine.
Marketed in 1932 as a decongestant, these amphetamine
isomers were the active ingredient in the popular Benzedrine inhaler, which quickly became known for its
stimulant properties. The addition of a second methyl
group created an even more potent amphetamine variant,
methamphetamine, sold as Methedrine. After the amphetamines became available in tablet form, they were used to
treat both narcolepsy, a condition characterized by sleep
attacks, and attention-deficit hyperactivity disorder
(ADHD), an apparent paradoxical effect (see below).
Amphetamine tablets also were used as appetite suppressants; d-amphetamine was marketed for this purpose as
Dexedrine in 1945, but the anorexiant effect faded rapidly
with repeated use. It was during World War II, however,
that the stimulant properties of the amphetamines became
widely recognized. Many American, German and Japanese
soldiers relied on the activating effects of these drugs
during prolonged military campaigns. The problem was
especially severe in Japan, where civilians used methamphetamine to keep up factory production for the war effort,
and large stockpiles of the drug continued to be available
after the war. By the 1960s, abuse of amphetamines had
spread throughout the industrialized world, and govern-
ments placed tight restrictions on the production and
distribution of these drugs; the now-infamous Benzedrine
inhaler was banned in 1959 as part of this effort. Despite
the crackdown, abuse of amphetamines continued, and to
make matters worse, authorities were soon confronted
with a drug problem they thought had been solved many
years earlier: cocaine abuse.
Cocaine occurs naturally in the leaves of a shrub, which
thrives along the eastern slopes of the Andes (Erythroxylon
coca) and other circumscribed regions of South America
(Erythroxylon novogranatense). Although natives of the
Andean highlands have been known for centuries to chew
coca leaves to increase energy and elevate the spirit, it was
not until the 1860s ] when cocaine could be extracted from
the leaves and refined to a pure form ] that cocaine use
spread to Europe and other continents. The coca extract
first gained popularity as a ‘feel-good’ additive to wines
and other beverages, though some physicians, including a
young Sigmund Freud, wrong-headedly recommended
intravenous cocaine to treat morphine addiction. The real
medicinal value of cocaine resided in its local anaesthetic
effects, which allowed it to be used for delicate eye and lung
surgery (see below).
By the end of the nineteenth century, cocaine’s easy
availability and favourable advertising, which included
many celebrity endorsements, led to widespread abuse.
Laws were passed to control its use and distribution.
Cocaine abuse did not resurface on a large scale until the
1970s when snorting cocaine powder became a way to get
‘high’ without needles or other dangerous paraphernalia.
In the mid-1980s, the introduction of a cheap, smokable
version of the drug known as ‘crack’ led to another surge in
cocaine abuse, creating more than 3 million addicts in the
United States alone. The amphetamines also experienced
an illicit upgrade, resulting in still more dangerous
variants, including a smokable and highly addictive form
of methamphetamine known as ‘ice’. More than 100 years
after the first widespread use of cocaine, stimulant abuse
continues to be a major, worldwide problem.
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Cocaine and Amphetamines
General Stimulants and an Increase in
the Availability of Norepinephrine
(Noradrenaline)
The amphetamines induce many physiological changes,
including an increase in heart rate and blood pressure,
dilatation of the bronchial tree, and increased respiration.
Because these effects mimic activation of the sympathetic
nervous system, the amphetamines and other drugs that
have these effects, including cocaine, are called sympathomimetics. The sympathetic nervous system is most active in
times of danger or stress to prepare the body for ‘fight or
flight’. Sympathomimetic drugs mimic this effect by
increasing the function of norepinephrine (noradrenaline),
the transmitter released by the sympathetic neurons
innervating the heart, vasculature, lungs and other internal
organs. Many of these drugs also act on epinephrine
(adrenaline), which when released into the bloodstream as
a hormone reinforces the effects of sympathetic activation.
Communication between a sympathetic nerve ending
and its target organ was one of the first events studied by
researchers interested in nervous system function. The
basic principles were established by the mid-1950s.
Norepinephrine is released from the transmitting or
presynaptic neuron to interact with receptors on the
receiving or postsynaptic cell. Almost immediately, the
norepinephrine returns to the presynaptic neuron by a
process known as reuptake. Under normal conditions,
reuptake prevents overstimulation of synaptic receptors
and resupplies the neuron with releasable norepinephrine.
Drugs like the amphetamines and cocaine activate
the sympathetic system by subverting the reuptake
mechanism.
Reuptake depends on transporter proteins located in the
presynaptic membrane. Each transporter is equipped with
a specialized site that binds a molecule of norepinephrine.
This site normally faces outward in anticipation of
norepinephrine release. When the released norpinephrine
attaches, ionic gradients across the neuronal membrane
cause the transporter to rotate inward. When the
norepinephrine enters intracellular fluid, it detaches from
the transporter, which then returns to its outward position
to repeat the process. In effect, the transporter operates as a
kind of revolving door moving norepinephrine from
outside to inside the neuron.
The amphetamines and cocaine are like norepinephrine
in that they attach to the transporter. But their attachment
changes the function of the transporter in dramatic, albeit
very different, ways. The amphetamines cause the transporter to release rather than take up norepinephrine. This
effect begins with an accumulation of amphetamine
molecules outside the neuron. The transporter, recognizing
them as norepinephrine, springs into action. As amphetamine is carried into the neuron, it detaches from the
transporter, and the transporter is now free to return to its
2
extracellular configuration. But because there already is a
large concentration of norepinephrine molecules inside the
neuron, they can attach to the transporter as it rotates
outward and they get deposited in the synapse. Another
factor reinforces this effect. As amphetamine accumulates
intracellularly, it enters the vesicles that store even more
norepinephrine. Under normal conditions, vesicular norepinephrine is held in place by an acidic or low pH, but
amphetamine, which is slightly basic, causes the pH to
increase and allows norepinephrine to leak from the
vesicles into the surrounding cytoplasm. This rise in
intracellular norepinephrine means that more is available
for outward transport. The amphetamines, therefore,
increase sympathetic activation by causing the outward
movement of norepinephrine from sympathetic nerve
endings.
Cocaine also binds to the norepinephrine transporter,
but unlike amphetamine, cocaine does not ride the
transporter into the neuron. Instead, the relatively large
size of the cocaine molecule prevents the transporter from
working. Without a functioning transporter, the neuron
loses its ability to regulate synaptic transmission. Thus,
norepinephrine released into the synapse when the neuron
becomes active will not be removed. Unlike the amphetamines, therefore, cocaine does not release norepinephrine
but allows it to accumulate in the synapse. Although this
action of cocaine contributes to its sympathomimetic
effects, the drug also acts on brain circuits that directly
control the sympathetic system, further enhancing a
sympathomimetic response.
Sympathomimetics as General
Stimulants
Even before the removal of Benzedrine inhalers, it became
clear that amphetamine-like drugs were not the ideal
treatment for bronchial congestion. The challenge was to
develop drugs that could dilate the bronchial tree without
interfering with the entire sympathetic system. A step in
this direction was made in the 1940s with the synthesis of
isoproterenol. Rather than increase synaptic norepinephrine like cocaine and the amphetamines, isoproterenol
stimulated a specific group of postsynaptic receptors. At
noradrenergic synapses, receptors are classified as either aadrenergic or b-adrenergic. Within each classification,
moreover, there are several subtypes. All respond to
norepinephrine, but each has a slightly different configuration such that a drug with a slightly different molecular
shape may activate only one or a few subtypes selectively.
The situation is analogous to locks in a building. A master
key may open them all, but individual keys may only open a
select few. Isoproterenol stimulates b-adrenergic receptors,
which are located on only some sympathetic target organs,
including the bronchial muscles. Thus, isoproterenol has a
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
Cocaine and Amphetamines
more selective sympathomimetic action than the amphetamines. Isoproterenol, moreover, does not readily cross
the blood]brain barrier, minimizing its central stimulant
properties. Although it is an effective antiasthmatic drug,
isoproterenol still has adverse cardiovascular effects
because b-adrenergic receptors are also located on heart
muscle. Stimulation of the heart, however, mainly occurs
via a subgroup of b-adrenergic receptors termed b1. With
further refinement of the isoproterenol molecule, it was
possible to devise drugs that could act more selectively on
the bronchial tree via b2 receptors and thereby reduce b1
cardiovascular effects. In addition, the realization that
asthma involves an inflammatory response led to the use of
glucocorticoids and other anti-inflammatory compounds
as an alternative treatment. Interestingly, nasal decongestion is now treated by drugs that stimulate the a1 subtype
of the a-adrenergic receptor.
Many sympathomimetics have been developed for the
treatment of a variety of ailments involving the heart, lungs
and other organs innervated by the sympathetic system.
These drugs not only are more selective but also lack the
powerful central stimulant actions of the early amphetamine prototypes. Some sympathomimetics, however, have
central stimulant effects, albeit less pronounced than
cocaine or the amphetamines. Perhaps the best known of
these other sympathomimetics is methylphenidate, marketed as Ritalin for the treatment of narcolepsy and
ADHD (see below).
Stimulation of Behavioural Arousal
and Vigilance
Research on the sympathetic nervous system provided an
important clue for understanding how sympathomimetic
drugs could alter brain function to induce a state of mental
alertness. Like the sympathetic system in the periphery, the
brain contains distinct groups of neurons that use
norepinephrine as a transmitter. These neurons, moreover,
are active during the same behavioural responses associated with sympathetic activation. It seemed likely,
therefore, that the brain noradrenergic system is also
active in response to cocaine and the amphetamines. This
hypothesis proved to be correct.
In the brain, many noradrenergic neurons originate in
the locus coeruleus, a brainstem nucleus that sends axons
to portions of the cerebral cortex and limbic system.
Cortical neurons process a wide range of cognitive, motor
and sensory information, whereas the limbic system
appears to regulate emotional behaviour. The locus
coeruleus, therefore, targets brain regions involved in
crucial behavioural outcomes. It influences how these
brain regions operate by modulating their level of
excitability through the release of norepinephrine. Highly
relevant or meaningful environmental events activate locus
coeruleus neurons. The resulting increase in norepinephrine release elevates cortical and limbic excitability, which
explains why such events increase our state of alertness.
Drugs like cocaine and the amphetamines mimic this
mental state by directly increasing the synaptic level of
norepinephrine in the brain just as they do in the
sympathetic nervous system (see above). This state of
alertness is manifest as an increase in arousal and vigilance.
Stimulation of Pleasure
The euphoria associated with the amphetamines and
cocaine appears to involve a brain transmitter chemically
similar to norepinephrine but found in different groups of
neurons. The transmitter is dopamine, and the neurons are
located in the ventral tegmental area of the midbrain.
These neurons send axons to portions of both the frontal
cortex, which plays a role in memory and other complex
aspects of information processing, and limbic system. An
important limbic target is the nucleus accumbens. Dopamine release in this area of the forebrain occurs in response
to naturally occurring pleasures such as food, novelty and
sex. The amphetamines and cocaine also increase synaptic
dopamine in the accumbens, suggesting that they, too,
cause the same neurochemical change as natural pleasures.
But because these drugs act directly on dopaminergic
transmission, they are likely to pack a much greater
dopamine ‘punch’ than pleasurable environmental stimuli,
which must travel from peripheral sensory organs through
several synaptic relays before activating the accumbal
dopamine system.
The amphetamines and cocaine increase dopamine
transmission in the same way that they influence norepinephrine: by attaching to transporter proteins. Both
structurally and functionally, the dopamine transporter
closely resembles the norepinephrine transporter. Thus,
the amphetamines bind to the dopamine transporter, get
carried inside the neuron, promote the leakage of
dopamine from intracellular vesicles, and, as the transporter returns to its extracellular configuration, intracellular
dopamine is transported outward into the synapse.
Cocaine, in contrast, prevents the dopamine transporter
from working, which allows synaptic dopamine to
accumulate. As with norepinephrine, therefore, both drugs
increase the level of synaptic dopamine. This similarity of
drug action in different neurons is not surprising in view of
the chemical similarity of dopamine and norepinephrine,
both of which are known as catecholamines.
Although they act by still different mechanisms, heroin
and nicotine also facilitate dopamine transmission in the
nucleus accumbens. In fact, all drugs of abuse that have
been tested produce this same neurochemical change,
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Cocaine and Amphetamines
suggesting that accumbal dopamine is a key factor in
drug addiction. The amphetamines and cocaine are just
two ] albeit very dramatic ] examples of drugs that usurp
a neuronal system normally involved in promoting
behaviour necessary for species survival and turning that
system into a mechanism for drug abuse.
It is important to stress that dopamine does not act
alone. Much like its catecholamine partner, norepinephrine, dopamine acts mainly by modulating the excitability of
target cells. In the nucleus accumbens, dopamine helps to
strengthen the response of neurons to other synaptic
inputs. Thus, the actions of dopamine must be considered
in terms of other ongoing neuronal activity. In addition, not all drugs of abuse ] not even the amphetamines
and cocaine ] elicit identical behavioural and emotional
responses; the differences reflect the different ways that
drugs alter brain neurochemistry beyond the catecholamines. It is especially noteworthy that serotonin, a
transmitter that shares some molecular features of the
catecholamines, also responds to many drugs of abuse
including the amphetamines and cocaine. In fact, cocaine is
just as effective in blocking the serotonin transporter and
thus increasing serotonin transmission as it is in increasing
synaptic dopamine and norepinephrine. Serotonin has
long been implicated in mood, suggesting that the
behavioural effects of cocaine reflect a complex interaction
of several transmitter systems. The amphetamines also
increase serotonin transmission, and they appear to do so
by attaching to the serotonin transporter and causing the
same changes as they do in dopamine and norepinephrine
neurons. Unlike cocaine, however, the amphetamines
have widely variable potencies in altering serotonin
transmission.
That dopamine is not the sole factor in a possible
pleasure circuit underlying addiction is evident in data
obtained from genetically engineered mice that lack the
gene for the dopamine transporter. If blockade of
dopamine reuptake is responsible for the pleasurable
properties of a drug like cocaine, then these mice should
not show any inclination to take the drug when given the
opportunity. Surprisingly, however, these animals will
work to obtain intravenous injections of cocaine in the
same way as genetically normal mice, suggesting that other
transmitters and other brain circuits participate in the
rewarding effects of cocaine.
Overdoses and Acute Psychosis
At high doses, the sympathomimetic effects of cocaine and
the amphetamines can be sufficiently severe to cause a
hypertensive crisis or even death. In fact, because of its
local anaesthetic action, cocaine has the added danger of
anaesthetizing heart muscle. With repeated drug use,
4
tolerance develops to the sympathomimetic effects, and
drug users are able to increase the dose to generate more
pronounced effects in the brain. An amphetamine addict or
‘speed freak’, for example, often takes the drug in binges or
‘runs’ characterized by intravenous injections of escalating
doses every few hours for several days. Unfortunately, the
drug-induced euphoria also fades with repeated use, and as
the dose escalates, an acute psychosis begins to emerge
characterized by paranoid delusions and auditory or visual
hallucinations.
In many respects, the drug-induced psychosis resembles
the symptoms of paranoid schizophrenia, which is one
reason why the behavioural effects of these drugs are
sometimes studied as models of the brain condition
underlying schizophrenia and related psychotic states.
In fact, the same drugs used to treat schizophrenia ] the socalled antipsychotic drugs ] can also alleviate the
stimulant-induced psychosis. The antipsychotic drugs
oppose the synaptic action of dopamine by blocking
dopamine receptors. This evidence forms the basis for the
view that dopamine dysfunction plays a key role in
paranoid psychosis. Abuse of stimulant drugs presumably
induces this mental condition by elevating synaptic
dopamine.
Although the mechanism linking dopamine and psychosis is far from settled, dopamine is known to modulate
neuronal excitability in areas of frontal cortex and limbic
system that process a wide range of cognitive information.
Disruption of this modulatory function, therefore, could
easily interfere with normal mental operations. It is also
interesting to note that apart from increasing cortical and
limbic dopamine, cocaine and the amphetamines also
elevate synaptic dopamine in the neostriatum, a sensorimotor integration area of the basal ganglia. Neostriatal
dopamine arises from the substantia nigra, which lies just
medial to the ventral tegmental area of the midbrain. Loss
of dopamine axon terminals in the neostriatum, which
occurs in Parkinson disease, leads to bradykinesia (slowness of movement) and other profound motor deficits. An
increase in neostriatal dopamine transmission, on the other
hand, has an activating effect on behaviour, which is often
manifest as a series of highly repetitive or stereotyped
motor patterns. In both amphetamine and cocaine
abusers, these motor patterns may include aimless walking,
compulsive sorting, and intense searching such as dismantling clocks, radios or television sets as if looking for
something. Perhaps the best-known example of cocaineinduced stereotypy is the searching behaviour of Sherlock
Holmes, whose cocaine habit was described by Dr Watson
(these characters were created by Arthur Conan Doyle in
the late 1800s when cocaine was readily available and
Doyle himself may have experienced the effects of the
drug). Like the drug-induced psychosis, many of the
stereotyped motor patterns become more intense with
repeated drug use and may actually become part of the
paranoid delusion.
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Cocaine and Amphetamines
Use as Therapeutic Agents
Neither cocaine nor the amphetamines have widespread
therapeutic value. Cocaine is most useful in medicine as a
local anaesthetic agent. This effect is complemented by a
strong vasoconstrictive action, which makes cocaine
especially valuable for anaesthetizing organs having a
dense vascular supply such as the eye and lungs to permit
delicate surgery. Freud’s proposal that cocaine be used to
treat morphine addiction seems laughable today. Freud
also recommended cocaine for the treatment of clinical
depression, but far safer and much more effective
antidepressant remedies have been available since the
1950s.
Although the amphetamines were developed specifically
for the treatment of asthma and related bronchial
conditions, the only remaining therapeutic value of these
drugs lies in their central stimulant properties. Because
d-amphetamine has more pronounced effects in the brain
than l-amphetamine, the d isomer is typically used for
narcolepsy and ADHD. Other treatments are available,
including methylphenidate (Ritalin), another sympathomimetic drug (see above), but these alternatives are not
dramatically better or different than d-amphetamine. For
narcolepsy, amphetamine prevents sleep attacks but
treatment is complicated by the potential for abuse as well
as the disruption of normal nighttime sleep.
In the case of ADHD, which is typically diagnosed in
childhood, it seems paradoxical that a stimulant would
have a beneficial effect in treating a condition characterized
by excessive motor activity and difficulty in focusing
attention. ADHD patients, however, are not really calmed
by amphetamine. They respond with an increase in arousal
and vigilance just like other individuals. The problem in
ADHD appears to be an inability to concentrate, which
results in hyperactivity. The drug-induced increase in
mental alertness, therefore, helps to overcome the concentration problem, which, in turn, helps to keep the
hyperactivity in check. Of course, a relatively high dose
would induce stereotyped motor activation, so stimulants
are prescribed in low doses for ADHD patients. Even at
low doses, however, the long-term consequences of
stimulant therapy begun in childhood continues to be a
major concern.
An early medicinal use for d-amphetamine was the
treatment of obesity. Dexedrine tablets were available as
appetite suppressants shortly after World War II. Despite
their popularity, they really had little lasting effect on food
intake because the decrease in appetite faded with
continued use. This tolerance meant that higher and more
dangerous doses of the drug were necessary to control
weight gain, and as the dose increased so too did the
possibility of long-term abuse and psychosis. Although the
amphetamines may see occasional use as anorectic agents,
they have been largely replaced by other drugs, including
some that act selectively on the serotonin system. A good
example is dexfenfluramine, marketed as Redux (USA),
which is a modified version of the original amphetamine
molecule but with relatively little ability to alter either
dopamine or norepinephrine transmission. Serotonin
systems in the brain are known to play a role in food
intake, but it is not clear how dexfenfluramine alters this
behaviour since the drug also slows the rate of gastric
emptying and increases body temperature, both of which
tend to suppress appetite.
Caffeine and Other Xanthines
Another group of drugs that combat fatigue, elevate mood,
and increase the capacity for work are the xanthines,
perhaps the most popular of which is caffeine. Like the
amphetamines, these stimulants have also been used to
treat asthma because they relax bronchial muscle, but their
therapeutic value is limited by their low potency. Even as
stimulants, the xanthines do not pack the wallop nor the
euphoria of cocaine or the amphetamines.
For coffee drinkers, the major source of caffeine is the
coffee bean, which is the fruit or seed of the Coffea arabica
plant. Caffeine also is found in Thea sinensis leaves, which
are used for making tea and which also contain theophylline, another xanthine. Other common sources of caffeine
include: cola drinks, which may contain extracts of the cola
nut, Cola acuminata, as well as any caffeine added in
production; chocolate, made from Theobroma cacao seeds,
which also contain the xanthine and theobromine; and
many over-the-counter analgesics and cold preparations,
which are made with a dose level of caffeine similar to that
in a small (4 oz) cup of coffee.
Caffeine, theophylline and theobromine, represent
different methylated versions of xanthine, which is a
purine compound structurally related to uric acid. All the
drugs in this category appear to influence neuronal
function by several mechanisms, but most of the research
has centred on caffeine. Despite its stimulant properties,
caffeine does not act directly on catecholamine neurons. It
may act indirectly, however, by inhibiting phosphodiesterase, an enzyme that metabolizes adenosine-3’5’- monophosphate or cyclic AMP. Because most, if not all, dopamine
and norepinephrine receptors influence cyclic AMP
production, a caffeine-induced change in cyclic AMP
levels could influence catecholamine transmission. This
cyclic AMP effect, however, occurs only at doses much
higher than those required to activate behaviour.
A more likely mechanism for the stimulant effect of
caffeine involves adenosine receptors. Adenosine is a
purine nucleotide that may function either as a transmitter
or as a modulator of other transmitters. Unlike caffeine,
adenosine depresses behaviour. It also depresses dopamine
release via receptors located on the axon terminals of
dopaminergic neurons. Caffeine, however, binds to
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5
Cocaine and Amphetamines
adenosine receptors and blocks their stimulation. Thus, by
acting as an adenosine receptor antagonist, caffeine
elevates dopamine release and activates behaviour.
Summary
Cocaine and the amphetamines are stimulants known for
their high risk of abuse. Their physiological effects were
first studied on norepinephrine-releasing neurons in the
sympathetic nervous system, which innervates the heart,
lungs and other internal organs. Both types of drugs attach
to the norepinephrine transporter, a protein in the plasma
membrane of noradrenergic neurons that removes norepinephrine from the synapse. Cocaine attaches in such a
way that the transporter is blocked, allowing synaptic
norepinephrine to accumulate. The amphetamines, in
contrast, keep the transporter working, but change its
mode of operation from removing norepinephrine to
releasing it. Both drug effects increase synaptic norepinephrine and thus mimic activation of the sympathetic
nervous system; hence, cocaine and amphetamines are
called sympathomimetics.
In the brain, these drugs increase norepinephrine
transmission by the same mechanism, which appears to
account for their ability to induce a state of arousal. They
also have euphoric effects that can play a role in addiction.
These effects have been linked to an increase in dopamine
transmission in limbic areas of the brain, although other
neurochemical systems are likely to play a role. Dopamine
may also be involved in the paranoid psychosis that
accompanies cocaine or amphetamine abuse. Therapeuti-
6
cally, cocaine has value as a local anaesthetic, whereas the
amphetamines are used to treat narcolepsy. Another
sympathomimetic drug, methylphenidate, shares some of
the actions of cocaine and amphetamine in the brain and is
used to treat attention deficit hyperactivity disorder by
improving concentration. Caffeine and other analogues
of xanthine are milder stimulants, which block brain
receptors for adenosine.
Further Reading
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Diego, CA: Academic Press.
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Science 251: 1580]1586.
Higgins ST and Katz JL (eds) (1998) Cocaine Abuse ] Behaviour,
Pharmacology, and Clinical Applications. San Diego, CA: Academic
Press.
Hyman SE (1996) Addiction to cocaine and amphetamine. Neuron 16:
901]904.
Leschner AI and Koob GF (1999) Drugs of abuse and the brain.
Proceedings of the Association of American Physicians 111: 99]108.
Seiden LS, Sabol KE and Ricaurte GA (1993) Amphetamine: effects on
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Tarter RE, Ammerman RT and Ott PJ (1998) Handbook of Substance
Abuse ] Neurobehavioral Pharmacology. New York: Plenum Press.
Volknow ND, Wang G-J, Fischman MW et al. (1997) Relationship
between subjective effects of cocaine and dopamine transporter
occupancy. Nature 386: 827]830.
White FJ and Kalivas PW (1998) Neuroadaptations involved in
amphetamine and cocaine addiction. Drug and Alcohol Dependence
51: 141]153.
Wise RA (1996) Addictive drugs and brain stimulation reward. Annual
Review of Neuroscience 19: 319]340.
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net