C H A P T E R

56
Neuropharmacology of Cocaine
and Amphetamine
Lori A. Knackstedt
University of Florida, Charleston, SC, USA

O U T L I N E

Introduction 573 Cocaine 575

Amphetamine 573 Cocaine and the Monoamine Neurotransmitters 576
Amphetamine and the Monoamine Cocaine and Non-Monamine Neurotransmitter
Neurotransmitters 574 Systems 576
Amphetamine and Non-Monamine Behavioral Effects of Cocaine 576
Neurotransmitter Systems 575
Conclusions 577
Behavioral Effects of Amphetamine 575

INTRODUCTION reuptake of DA and NE as well as stimulating their

release from nerve terminals. d-amphetamine has been
Cocaine and amphetamine are classified as psychosti- shown to be more potent than l-amphetamine both
mulants, drugs which increase arousal, alertness, and behaviorally and pharmacologically. Amphetamine
motor activity. Humans report that these drugs produce was first synthesized in 1887 and the racemic mixture
a significant euphoria and are highly addictive. Both was marketed in the form of the Benzedrine inhaler
drugs are agonists of monoamine neurotransmitters, for the treatment of asthma and nasal congestion.
but work through different mechanisms to increase Amphetamine was made available in tablet form in
dopamine (DA), norepinephrine (NE), and serotonin 1930, when it was used as a treatment for narcolepsy
transmission. This chapter will discuss the major effects and also by the military to increase wakefulness in the
of each drug on the monoamine systems as well as other World War II soldiers. Following the World War II,
neurotransmitter systems, and their behavioral effects in America experienced a surge in recreational amphet-
humans and experimental animals. amine use that lasted until the 1970s. Today, the main
clinical application of amphetamine is the treatment of
attention deficit hyperactivity disorder (ADHD). The
AMPHETAMINE modern formulation of amphetamine for ADHD treat-
ment is a combination of racemic amphetamine and
Amphetamine is a chiral compound; the two stereo- d-amphetamine (e.g. Adderall). Also in the amphet-
isomeric forms of amphetamine are levoamphetamine amine class is methamphetamine, or “meth,” the
(L-amphetamine) and dextroamphetamine (D-amphet- N-methylated form of the drug. Both Adderall and
amine). Both stereoisomers are indirect agonists of the meth are commonly abused today. While meth
catecholaminergic systems, working to prevent the shares many neuropharmacological properties with

Biological Research on Addiction, Volume 2

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574 56. NEUROPHARMACOLOGY OF COCAINE AND AMPHETAMINE

d-amphetamine, meth is discussed in a separate chapter who showed that there is a direct relationship between
in this volume. the efficacy of amphetamine to increase DA efflux and
the kinetic parameters of their interaction with the
DAT, corroborating the exchange diffusion model of
AMPHETAMINE AND THE MONOAMINE amphetamine action. It was also shown that the
NEUROTRANSMITTERS exchange diffusion model applies to the actions of low
dose amphetamine, while at high doses, amphetamine
Amphetamine increases dopaminergic transmission saturates the transporter binding site and enters the
through its actions on the DA transporter (DAT), both nerve terminal via passive diffusion.
by preventing the reuptake of released DA and by The ability of amphetamine to induce the release of
reversing the transporter to produce an efflux of DA. DA through DAT relies on sufficient concentrations of
These effects are most prominent along the mesocortico- DA being available in the cytoplasm, outside of synaptic
limbic DA pathway which sends projections from the vesicles. One way in which amphetamines increase cyto-
ventral tegmental area (VTA) of the midbrain to the plasmic DA is by inhibiting the vesicular monoamine
nucleus accumbens, amygdala, and prefrontal cortex transporter-2 (VMAT-2) and thereby disrupting the
(PFC). Using a slice preparation, in 1975 Heikkila and storage of DA into synaptic vesicles. In a second mech-
colleagues demonstrated that amphetamine inhibits anism of increasing interneuronal DA concentrations,
the uptake of DA in the striatum and cortex. d-amphet- Sulzer and Rayport reported that amphetamine induces
amine was shown to be 3–4 times more potent than l- the release of DA from storage vesicles due to the fact
amphetamine in the striatum, but not the cortex, in that it’s a weak base and reduces the synaptic vesicle
agreement with the finding that d-amphetamine has pH gradient. This finding led to the authors proposing
a greater affinity for striatal DAT than does l-amphet- the “weak base model” of amphetamine action, which
amine. Amphetamine is also capable of inducing the is not mutually exclusive from the exchange diffusion
release of DA in a calcium-independent manner. This model. In the weak base model, amphetamine enters
release is also sensitive to the tyrosine hydroxylase synaptic vesicles due to its lipophilicity. The internal
inhibitor, a-methyl-r-tyrosine (AMPT), but not reser- environment of the synaptic vesicles is acidic while
pine, which prevents DA from being packaged into vesi- amphetamine is a weak base, leading to the donation
cles. This would indicate that amphetamine is affecting of Hþ ions to the amine group on an amphetamine
the non-vesicular, spontaneous release of DA from the molecule. The consequent decrease in free Hþ ions
cytoplasm, as opposed to the calcium-dependent, vesic- inside the vesicles increases the pH and thus decreases
ular release that occurs following an action potential. In the pH gradient between vesicle interior and the cyto-
support of this hypothesis, an in vivo microdialysis plasm, promoting the efflux of DA into the cytoplasm,
study demonstrated that the inhibition of action poten- where it can be exported into the synapse either by
tials with tetrodotoxin (TTX) did not affect the ability passive diffusion across the presynaptic membrane or
of amphetamine to increase DA concentrations in the through carrier-mediated transport (as described by
striatum. It was first hypothesized that amphetamine the exchange diffusion model).
induces the spontaneous release of DA by increasing Amphetamine also prevents the reuptake of NE by
the concentration gradient inside the neuron and thus the NE transporter (NET). NE-containing neurons are
DA enters the synapse via passive diffusion. However, localized in brainstem nuclei such as the locus coeruleus
in 1979 Fischer and Cho demonstrated that in the stria- and noradrenergic axons project diffusely to almost
tum, amphetamine accomplishes the spontaneous every part of the brain. Like DA, inhibition of uptake
release of DA by acting as a substrate for the transporter is not the primary mechanism by which amphetamine
and is taken up into the terminal in a saturable, stereose- increases NE synaptic concentrations; NE is also
lective manner. In accordance with this finding, DAT released from terminals by amphetamine. In 1974,
inhibitors prevent amphetamine from releasing DA Azzaro and colleagues found that amphetamine-
into the synapse. Combined with the finding that the induced release of NE was prevented by blocking amine
DA transporter can transport DA out of the neuron transporters, and it was subsequently found that
and into the synapse under certain conditions, an amphetamine induces carrier-mediated release of NE.
“exchange diffusion model” of amphetamine action It has been suggested that since amphetamine has
was proposed. This model proposes that amphetamine more efficacy at the NET than at the DAT or the sero-
binds to the DAT and translocated into the cytoplasm. tonin transporter (SERT), NE mediates the majority of
Because the binding site on the DAT is now located the subjective effects of amphetamine. This idea is sup-
inside the terminal, it is capable of binding intracellular ported by the finding that DA receptor antagonists do
DA to transport it out of the terminal, into the synapse. not attenuate the subjective affects of amphetamine in
This hypothesis was verified by Parker and Cubeddu, humans (see below).

IV. NEUROPHARMACOLOGY/IMAGING/GENETICS
 COCAINE 575
While it has been suggested that amphetamine inter- stereotyped behavior. Amphetamine is also a potent rein-
acts with the SERT in a similar manner as it does with the forcer of operant behavior in animals; animals will
DAT and NET, there exists a paucity of research on this readily acquire amphetamine self-administration. DA
subject. Amphetamine has been shown to increase sero- release in the nucleus accumbens has been shown to be
tonin release in a manner consistent with the exchange required for amphetamine self-administration in rodents,
diffusion model and increased levels of serotonin have indicating that it is amphetamine’s ability to increase the
been measured in the striatum of animals treated with release of this neurotransmitter in this brain area that
amphetamine. Additionally, the locomotor-stimulating underlies its reinforcing abilities.
effects of amphetamine depend on serotonergic trans- Humans report that amphetamine produces
mission in both animals and humans. euphoria, increases alertness and confidence, and
reduces fatigue. The role of DA in these effects is not
clear, with some studies showing that neuroleptic drugs
AMPHETAMINE AND NON-MONAMINE which antagonize D2 receptors attenuate the subjective
NEUROTRANSMITTER SYSTEMS effects of amphetamine in humans but other studies
showing no effect of such drugs on the ability of amphet-
Systemic administration of amphetamine increases amine to induce arousal and euphoria. Thus, it has been
glutamate transmission in regions of the mesolimbic concluded that DA transmission may be necessary but
DA system such as the nucleus accumbens and VTA. not sufficient to mediate the subjective effects of
However, direct administration of amphetamine into amphetamine. It is likely that the subjective effects
the nucleus accumbens or VTA produces either of amphetamine in humans results from a combination
a delayed elevation, or even a reduction, in extracel- of enhanced DA and NE transmission as the NET inhib-
lular glutamate. This suggests that systemically admin- itor atomoxetine attenuates some of d-amphetamine’s
istered amphetamine acts in other brain regions to subjective and physiological effects in humans. Addi-
activate glutamatergic afferents to the VTA and tionally, the endogenous opioid system has recently
nucleus accumbens. In the VTA, the effect of amphet- been implicated in the actions of amphetamine; treat-
amine is DA-dependent and prevented by PFC lesions, ment with the opioid antagonist naltrexone attenuated
suggesting that PFC projection to the VTA underlies the subjective effects of amphetamine in humans.
the role of VTA glutamate in amphetamine-induced
locomotion. In agreement with these preclinical
studies, humans given minocycline, an antibiotic COCAINE
which interferes with glutamatergic transmission,
showed decreased subjective effects of amphetamine. Cocaine is an alkaloid first isolated from the leaves of
Additionally, the k-opioid agonist, U-69593, decreases the coca plant in the nineteenth century. Subsequently,
amphetamine-evoked behaviors, most likely by pre- cocaine was used clinically as a local anesthetic, espe-
venting increases in DA and glutamate levels in the cially for nasal and ophthalmic surgeries. Sigmund
nucleus accumbens. Freud popularized cocaine in 1884 by publishing Uber
Coca, in which he recommended its use in the treatment
of alcoholism, morphine addiction, and depression.
BEHAVIORAL EFFECTS Freud, a cocaine user himself, wrote that cocaine
OF AMPHETAMINE produces “exhilaration and lasting euphoria, which in
no way differs from the normal euphoria of the healthy
Low doses of amphetamine administered to rodents person. This result is enjoyed without any of the
produce increased locomotor activity, rearing, sniffing, unpleasant after-effects that follow exhilaration brought
and head waving. Higher doses cause animals to engage about by alcohol.” Freud also proposed that cocaine
in repetitive, pointless behaviors termed stereotypies. For was not addictive and produced no harmful effects on
example, rats may sniff the same area of their cage repeat- the body: “It seems to me noteworthy – and I discovered
edly, lick or gnaw, or show repetitive head/limb move- this in myself and in other observers who were capable
ments. DA transmission has been strongly implicated in of judging such things – that a first dose or even repeated
amphetamine-induced locomotor enhancement and doses of coca produce no compulsive desire to use the
stereotypy. Injections of both DA and amphetamine stimulant further; on the contrary, one feels a certain
directly into the nucleus accumbens produce increased unmotivated aversion to the substance.” Freud was
locomotor activity while lesions of the dopaminergic cells proved to be incorrect on this matter, and in the United
in this brain area prevent amphetamine from increasing States, President Taft declared cocaine to be “Public
locomotion. Similar experiments implicate the dorsal Enemy Number 1” in 1910. This in turn led Congress
striatum in the ability of amphetamine to produce to past the Harrison Narcotic Act, which prohibited the

IV. NEUROPHARMACOLOGY/IMAGING/GENETICS
576 56. NEUROPHARMACOLOGY OF COCAINE AND AMPHETAMINE

use of cocaine. Cocaine continued to be a popular recre- animals; however, stereotypy is less pronounced after
ational drug throughout the twentieth century America. cocaine than after amphetamine. Antagonists of the
In the 1980s, the smokable base form of cocaine was DA system and the destruction of the mesolimbic DA
developed and termed “crack.” This form of the drug circuit disrupt the ability of cocaine to induce locomotor
is significantly less expensive than powder cocaine, activation and stereotypy and to maintain operant self-
thus making it available to poorer populations. Like administration.
amphetamine, cocaine produces a significant euphoria Humans report that cocaine produces euphoria,
and increased locomotion, largely through actions at alertness, aggressiveness, and self-confidence. In
monoamine transporters as will be discussed below. humans, it has been shown that pretreatment with
a single dose of the D1/D5 antagonist ecopipam atten-
uates the euphoric effects of intravenous cocaine when
COCAINE AND THE MONOAMINE administered 2 h prior to cocaine. Additionally,
NEUROTRANSMITTERS repeated dosing of ecopipam attenuates cocaine-
induced euphoria when ecopipam is given 15 h prior
Cocaine increases monoamine transmission by acting to cocaine. However, one study has shown that
as a reuptake blocker for the transporters for DA, NE, pretreatment with ecopipam 20 h prior to dosing with
and serotonin. Cocaine binds to SERTs with approxi- intravenous cocaine does not alter the subjective effects
mately five-fold greater potency than at DATs and binds of cocaine. Other researchers, however, showed that
to NETs with approximately three-fold lower affinity ecopipam enhanced the euphoria produced by smoked
than DATs. This difference in selectiveness for trans- cocaine. The D2 antagonists haloperidol and risperi-
porters of cocaine versus amphetamine likely contrib- done weaken the self-reported “high” produced by
utes to the different behavioral effects produced by cocaine. However, since the degree of D2 blockade by
amphetamine and cocaine, as amphetamine have very risperidone is higher than the reduction in subjective
little affinity for SERTs and high affinity for NETs. The effects, the authors of this study proposed that
blockade of transporter proteins by cocaine leads to other receptors must be involved in mediating the
the accumulation of the transmitter substances in the euphoria/drug high produced by cocaine. Another
synapse. drug used to investigate the role of DA in the
subjective effects produced by cocaine is isradipine,
a dihydropyridine-class calcium channel antagonist
COCAINE AND NON-MONAMINE which inhibits cocaine-mediated increases in mesolim-
NEUROTRANSMITTER SYSTEMS bic DA. Isradipine (up to 30 mg) was shown to have
no effect on cocaine’s subjective effects in cocaine-
Cocaine also increases extracellular glutamate levels dependent individuals. The effects of disulfiram on
in the VTA, nucleus accumbens, striatum, and PFC. cocaine-induced euphoria also sheds light on the role
However, the increase in glutamate levels following of DA. Disulfiram is a drug which is typically used to
acute cocaine in the VTA and nucleus accumbens are treat alcoholism due to its ability to inhibit a key
dependent on DA transmission and can be mimicked enzyme in the metabolism of alcohol, producing severe
by administration of a DA agonist alone. Similarly, nausea in patients who consume alcohol with disul-
cocaine is an acetylcholine agonist but in a DA- firam. Disulfiram also inhibits the enzyme that converts
dependent manner. Recently, the combination of DA to NE, DA b-hydroxylase, causing increased
cocaine with histamine antagonists has been shown synaptic DA relative to NE levels. Following disulfiram
to be more readily self-administered by primates. treatment, cocaine euphoria ratings have been found to
The increased reinforcing properties of this drug be significantly reduced in human volunteers receiving
combination was shown not to be DA-dependent, intravenous cocaine, an effect attributed to its affect on
indicating an interaction with the histamine system DA. Taken together, the above experiments indicate
is involved. In support of this idea, it has been found that as with amphetamine, cocaine’s subjective effects
that in genetically engineered mice lacking histamine, involve DA, but it is likely that other neurotransmitters
cocaine produces less locomotor behavior than in wild are involved as well.
type control mice. Serotonin likely plays a role in the subjective effects of
cocaine since the depletion of tryptophan (the precursor
to serotonin) attenuates the reported euphoria produced
BEHAVIORAL EFFECTS OF COCAINE by intranasal cocaine. The endogenous opioid system
has also been implicated in the actions of cocaine in
Like amphetamine, cocaine increases locomotor humans; naltrexone treatment attenuated the rating of
activity and stereotyped behaviors in experimental some of the behavioral effects of cocaine.

IV. NEUROPHARMACOLOGY/IMAGING/GENETICS
 FURTHER READING 577

CONCLUSIONS Azzaro, A.J., Ziance, R.J., Rutledge, C.O., 1974. The importance of
neuronal uptake of amines for amphetamine-induced release of
3H-norepinephrine from isolated brain tissue. The Journal of Phar-
While both cocaine and amphetamine increase mono- macology and Experimental Therapeutics 189, 110–118.
amine neurotransmission, significant pharmacody- Butcher, S.P., Fairbrother, I.S., Kelly, J.S., Arbuthnott, G.W., 1988.
namic differences exist. For example, amphetamine is Amphetamine-induced dopamine release in the rat striatum: an in
more potent at the NET than at the DA or SERTs, while vivo microdialysis study. Journal of Neurochemistry 50, 346–355.
Fischer, J.F., Cho, A.K., 1979. Chemical release of dopamine from
cocaine is most effective in preventing serotonin uptake.
striatal homogenates: evidence for an exchange diffusion model.
Amphetamine also induces the release of these mono- The Journal of Pharmacology and Experimental Therapeutics 208,
amines from the nerve terminal into the synapse, while 203–209.
cocaine does not. These differences in pharmacody- Heikkila, R.E., Orlansky, H., Mytilineou, C., Cohen, G., 1975.
namics likely underlie the different behavioral effects Amphetamine: evaluation of d- and l-isomers as releasing agents
and uptake inhibitors for 3H-dopamine and 3H-norepinephrine in
of amphetamine and cocaine in humans and animals.
slices of rat neostriatum and cerebral cortex. The Journal of Phar-
macology and Experimental Therapeutics 194, 47–56.
Parker, E.M., Cubeddu, L.X., 1988. Comparative effects of amphet-
SEE ALSO amine, phenylethylamine and related drugs on dopamine efflux,
dopamine uptake and mazindol binding. The Journal of Pharma-
cology and Experimental Therapeutics 245, 199–210.
Animal Models of Drug Addiction: Cocaine, The
Raiteri, M., Cerrito, F., Cervoni, A.M., Levi, G., 1979. Dopamine can be
Mesolimbic Dopamine Reward System and Drug released by two mechanisms differentially affected by the dopa-
Addiction mine transport inhibitor nomifensine. The Journal of Pharma-
cology and Experimental Therapeutics 208, 195–202.
Rothman, R.B., Baumann, M.H., Dersch, C.M., et al., 2001. Amphet-
List of Abbreviations amine-type central nervous system stimulants release norepi-
nephrine more potently than they release dopamine and serotonin.
DA dopamine
Synapse 39, 32–41.
NE norepinephrine
Sulzer, D., Maidment, N.T., Rayport, S., 1993. Amphetamine and other
DAT dopamine transporter
weak bases act to promote reverse transport of dopamine in
NET norepinephrine transporter
ventral midbrain neurons. Journal of Neurochemistry 60, 527–535.
SERT serotonin transporter
Vanderschuren, L.J.M.J., Kalivas, P.W., 2000. Alterations in dopami-
ADHD attention deficit hyperactivity disorder
nergic and glutamatergic transmission in the induction and
D2 dopamine receptor 2
expression of behavioral sensitization:a critical review of preclin-
PFC prefrontal cortex
ical studies. Psychopharm 151, 99–120.
VTA ventral tegmental area
White, F.J., Kalivas, P.W., 1998. Neuroadaptations involved in
amphetamine and cocaine addiction. Drug and Alcohol Depen-
dence 51, 141–153.

Further Reading
Arnold, E.B., Molinoff, P.B., Rutledge, C.O., 1977. The release of
endogenous norepinephrine and dopamine from cerebral cortex Relevant website
by amphetamine. The Journal Pharmacology and Experimental
Therapeutics 202, 544–557. www.nida.nih.gov – National Institute on Drug Abuse.

IV. NEUROPHARMACOLOGY/IMAGING/GENETICS