Addiction and the brain
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to a greater understanding of the neurobiologi-
cal processes that underlie drug abuse and addiction. These suggest that multiple
neurotransmitter systems may play a key role in the development and expression of
drug dependence. These advances in our knowledge promise not only to help us
identify the underlying cause of drug abuse and dependence
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Review
Synthèse
From *the Centre for
Addiction and Mental
Health, Toronto, Ont.;
the Departments of
†Pharmacology, ‡Medicine
and §Psychiatry, University
of Toronto, Toronto, Ont;
and ¶the Centre for Research
in Women’s Health,
Sunnybrook & Women’s
College Health Sciences
Centre, Toronto, Ont.
This article has been peer reviewed.
CMAJ 2001;164(6):817-21
Abstract
R
ECENT SCIENTIFIC ADVANCES HAVE LED
to a greater understanding of the neurobiologi-
cal processes that underlie drug abuse and addiction. These suggest that multiple
neurotransmitter systems may play a key role in the development and expression of
drug dependence. These advances in our knowledge promise not only to help us
identify the underlying cause of drug abuse and dependence, but also to aid the
development of effective treatment strategies.
T
he chemicals that humans abuse are structurally diverse and produce dif-
ferent behavioural effects in the user. Nevertheless, all share the common
feature that they can modulate the brain reward system that is fundamental
to initiating and maintaining behaviours important for survival (e.g., eating, sexual
activity).
1
Researchers first postulated that specific neural circuits within the brain
were involved in the regulation of reward processes when early studies demon-
strated that rats would press a lever in order to obtain electrical stimulation of cer-
tain areas of the brain, but not others. The medial forebrain bundle (MFB), which
connects the ventral tegmental area (VTA) to the nucleus accumbens (NAcc), was
the site first identified in this way (Fig. 1). Other neurotransmitter pathways pro-
jecting from the VTA and the NAcc that innervate additional limbic (e.g., the
amygdala) and cortical areas of the brain, which are important for the expression of
emotions, reactivity to conditioned cues, planning and judgement (Fig. 1), have also
been implicated in reward. Although the MFB consists of neurons that contain
dopamine, noradrenaline and serotonin (5-HT), it is the dopaminergic projection
that has been most closely implicated in reward. Thus, natural and artifical rewards
(food, sex, drugs of abuse) have been shown to activate this dopaminergic pathway,
also known as the mesolimbic dopamine pathway, causing an increase in dopamine
levels within the NAcc. From an evolutionary perspective, this brain reward circuit
has ensured survival by giving priority to essential actions such as reproduction.
Drugs of abuse are able to exert influence over the brain reward pathway either by
directly influencing the action of dopamine within the system, or by altering the
activity of other neurotransmitters that exert a modulatory influence over this
mesolimbic dopaminergic pathway. γ-Aminobutyric acid (GABA), opioid, seroton-
ergic, cholinergic and noradrenergic neurotransmitter pathways have all been
shown to interact at various points along the mesolimbic dopaminergic pathway
and to modulate its activity. Some of the major elements in the brain reward circuit
are illustrated in Fig. 2.
Advances in our knowledge of the mechanisms by which various drugs of abuse al-
ter the activity of this neuroanatomical system have helped our understanding of the
neurobiological underpinnings of addiction and in the development of effective treat-
ment strategies. To illustrate some of the advances in research and the application of
this knowledge, a brief review of the literature is provided. This has been subdivided
by drug class and presented in order of the prevalence of each drug’s use in Canada.
Nicotine
Nicotine is the main psychoactive constituent found in tobacco that has been
shown to be responsible for its behavioural and physiological effects, which can lead
Addiction and the brain: the role
of neurotransmitters in the cause
and treatment of drug dependence
Denise M. Tomkins,
*†
Edward M. Sellers
*†‡§¶
CMAJ • MAR. 20, 2001; 164 (6)
817
© 2001 Canadian Medical Association or its licensors
to addiction. Nicotine exerts its effects in the brain by act-
ing on a specific type of receptor for the neurotransmitter
acetylcholine, known as the nicotinic receptor. Some nico-
tinic receptors are located on the cell bodies of dopamine
neurons within the VTA, and activation of these receptors
increases the activity of these dopamine neurons, leading to
an increase in dopamine release in the NAcc, which is
thought to mediate reward.
2,3
Nicotinic receptors are also
located on other neurotransmitter inputs to the VTA and
further increase dopamine release by removing the in-
hibitory influence that these other neurotransmitter inputs
exert over the dopamine neurons (Fig. 2). The role of the
mesolimbic dopamine system in nicotine reward has been
clearly demonstrated in animals, because both the adminis-
tration of dopamine blockers and the destruction of the
mesolimbic dopamine pathway with selective neurotoxins
attenuate nicotine self-administration.
4
Similarly, research in humans suggests a role for
dopaminergic processes in regulating the reinforcing ef-
fects of nicotine. In the limited number of studies con-
ducted to date, administration of dopamine blockers has
been found to alter smoking behaviour. However, in the
case of humans, dopamine blockade leads to a compen-
satory increase in, and not suppression of, smoking.
4
Other
neurotransmitter systems have also been implicated, in-
cluding the opioid and cholinergic systems. Thus, adminis-
tration of either an opioid or nicotinic antagonist reduced
smoking behaviour in some, but not all, studies reported.
5,6
The most commonly used pharmacological approach for
treating nicotine dependence is the use of nicotine replace-
ment therapies, such as the nicotine patch, which reduce
craving by maintaining plasma nicotine levels.
7
However,
further advances in our understanding of the neurobiologi-
cal factors underlying nicotine dependence have led to the
introduction of new pharmacotherapies for its treatment.
The nonnicotine medication, bupropion, which was origi-
nally developed as an antidepressant, has recently been ap-
proved as an aid to smoking cessation. Its primary mecha-
nisms of action are reported to be via interactions with the
noradrenergic and dopaminergic systems implicated in
nicotine dependence, however, the nature of its mechanism
of action is poorly understood at the present time. Multiple
clinical trials have demonstrated that bupropion is an effec-
tive aid in facilitating smoking cessation, although, in the
majority of cases, the abstinence from smoking was not
maintained in the long term.
8
Alcohol
Along with nicotine, alcohol is one of the most com-
monly used psychoactive substances in Canada. Multiple
neurotransmitter systems play a role in mediating the be-
havioural effects of alcohol that have been linked to its
abuse and dependence.
9
This undoubtedly reflects the fact
that alcohol produces many pharmacological effects within
the brain. Nonetheless, the mesolimbic dopamine system
has been shown to play a role in the rewarding effects of al-
cohol. Alcohol is similar to other abused substances in that
it increases NAcc dopamine release, and blocking the ef-
fects of dopamine reduces alcohol intake by animals.
9
Fur-
thermore, innate differences in central dopaminergic neu-
Tomkins and Sellers
818
JAMC • 20 MARS 2001; 164 (6)
Fig. 1: Schematic diagram of the human brain that highlights
some of the main brain areas and neurotransmitter pathways
implicated in reward processes.
Lianne Friesen
Prefrontal
cortex
Planning,
judgement
Frontal
cortex
Nucleus
accumbens
Medial forebrain
bundle
Ventral tegmental
area
Reward
Emotions,
conditioned effects
Amygdala
Fig. 2: Schematic diagram that represents the dopamine path-
way projecting from the ventral tegmental area (VTA) to the
nucleus accumbens (NAcc), indicating how substances of
abuse can alter the activity of this pathway to produce their
rewarding effects.
Lianne Friesen
Dopamine cell body
Activation results in the release of
dopamine in the NAcc.
Opioids, nicotine and alcohol can
stimulate the dopamine cell body
directly by interacting with
specific receptors on its surface
and/or indirectly by altering the
activity of other neurotransmitter
inputs projecting from distal brain
areas.
Dopamine transporter
recycles some of the released
dopamine back into the nerve
terminal.
Cocaine and amphetamines
block reuptake of dopamine,
which accumulates in the synapse
where it can further stimulate
dopamine receptors.
Amphetamines also cause
dopamine release.
Dopamine
Released dopamine interacts
with postsynaptic dopamine
receptors, resulting in reward.
GABA interneuron
tonically suppresses dopamine
cell firing, resulting in reduced
NAcc dopamine release.
Opioids, nicotine and alcohol
can block the inhibitory control
exerted by these neurons over
the VTA dopamine cell bodies,
resulting in increased VTA
dopamine activity.
VTA
NAcc
rotransmission have been linked to high levels of alcohol
drinking in selectively bred rodent lines.
10
However, ani-
mals will continue to self-administer alcohol if the
mesolimbic dopamine pathway is destroyed using a selec-
tive neurotoxin. This suggests that additional mechanisms
are involved in regulating the rewarding effects of alcohol.
Other neurotransmitter systems that have been implicated
include the serotonergic, glutamatergic, GABAergic and
opioid systems. Thus, alcohol directly binds to and modu-
lates the activity of various specific receptors of these neu-
rotransmitter systems (e.g., 5-HT
3
, GABA
A
and N-methyl-
D
-aspartate [NMDA] receptors) that are located within the
brain reward pathway and can indirectly modulate
mesolimbic dopamine activity via feedback mechanisms, for
example, by increasing VTA activity through decreasing
the suppressant influence that GABAergic inputs exert over
them (Fig. 2).
11
Altered central dopamine function has also been impli-
cated as influencing the propensity for alcohol consump-
tion in humans, at least in some populations.
12
Human ge-
netic studies suggest that an association exists between
alcoholism and both the dopamine D
2
receptor and the
dopamine transporter. This is supported by brain imaging
studies that have reported alterations in both D
2
receptor
and dopamine transporter densities in the brains of alco-
holics.
13–15
These findings could have important implica-
tions for treatment, because recent work suggests that in-
creased density of D
2
receptors may be a predictor of
vulnerability to relapse in alcohol-dependent patients.
16
As
highlighted by animal studies, other neurotransmitter sys-
tems have similarly been implicated as underlying the
propensity to consume alcohol in humans, and the newer
pharmacotherapies that have been approved for the treat-
ment of alcohol dependence mediate their effects via some
of these systems.
The most common treatment strategies for alcoholism
that are currently employed are psychosocial interventions
and self-help groups (e.g., Alcoholics Anonymous), because
the use of pharmacotherapies has been limited until re-
cently by the lack of effective therapeutic agents. In the
past, pharmacological agents were used mainly to alleviate
the symptoms of acute withdrawal (e.g., benzodiazepines
and β-blockers to reduce anxiety), to prevent the complica-
tions of withdrawal (e.g., anticonvulsant agents to prevent
seizures) or to provide an aversive experience when alcohol
was ingested (e.g., disulfiram).
17
More recently, 2 drugs
have been approved for clinical use that are aimed specifi-
cally at reducing alcohol consumption. Naltrexone, an opi-
oid receptor antagonist, reliably reduces alcohol intake in
preclinical animal studies, which is consistent with the im-
portance of the opioid system in modulating the rewarding
effects of alcohol. Within North America, naltrexone is the
most widely used pharmacotherapy for the treatment of al-
coholism. Initial clinical trials reported that naltrexone sig-
nificantly improved abstinence rates and reduced relapse
rates in recently abstinent alcoholics.
18,19
Self-reports indi-
cated that subjects had a reduced desire to drink and, in
cases where alcohol was consumed, subjects reported a
dampening in the hedonic properties of alcohol. More re-
cent clinical trials, however, have suggested that compli-
ance issues are important in determining treatment efficacy
with naltrexone, and strategies for improving treatment
outcomes are the subject of current research.
20
Acamprosate is the drug of choice for the treatment of
alcoholism in Europe. It is a structural analogue of the neu-
rotransmitter GABA, which is reported to exert its effects
mainly via an interaction with the NMDA receptor. As
noted earlier, the NMDA receptor is one of the specific re-
ceptors located within the brain reward pathway to which
alcohol directly binds, and it can indirectly modulate
mesolimbic dopamine activity. This is relevant to alco-
holism because hyperexcitability in the NMDA system has
been shown to occur following long-term alcohol use and
has been linked with the expression of withdrawal on cessa-
tion of drinking. Clinical testing of the efficacy of acam-
prosate in the treatment of alcoholism has been exten-
sive.
21–25
The outcomes of these studies have consistently
demonstrated that the use of acamprosate significantly im-
proves abstinence rates and reduces the number of relapses.
In contrast to naltrexone, compliance issues do not appear
to be as much of a concern with acamprosate. A large mul-
ticentre trial with acamprosate is currently underway in the
United States.
26
In contrast to many other abused substances, the effects
of alcohol on the brain reward system are quite complex, as
highlighted earlier, with many neurotransmitter systems
being implicated. This presents unique challenges for the
development of effective pharmacotherapies for the treat-
ment of alcohol abuse and dependence. It is likely that
pharmacological interventions directed at altering the in-
fluence of one neurotransmitter system on the rewarding
effects of alcohol may have limited utility because of com-
pensatory changes in the other regulatory neurotransmitter
systems. This is supported by the experiences reported with
various pharmacotherapeutic agents used singly in the clin-
ical setting, in which small but significant improvements in
alcohol-drinking indices were noted.
17
Thus, a broader
pharmacotherapeutic approach using a combination of
drugs with different mechanisms may prove to be more ef-
fective. A recent study supports the notion that such a
treatment strategy can improve patient outcomes
27
and fur-
ther improve compliance by reducing the reported fre-
quency of side effects. Although there has been limited re-
search in this area, these initial findings support the need
for further work.
Stimulants
Stimulant drugs, such as cocaine and amphetamines, are
substances that typically cause heightened feelings of well-
being and euphoria, and an increased state of arousal. As
with most drugs abused by humans, the psychostimulants
Addiction and the brain
CMAJ • MAR. 20, 2001; 164 (6)
819
are similarly self-administered by animals, and most of the
information regarding their mechanism of action has been
derived from animal research. From a biochemical perspec-
tive, the major mechanism by which the amphetamines and
cocaine potentiate the actions of dopamine within the
mesolimbic system is by inhibiting dopamine reuptake into
the nerve terminals via the dopamine transporter.
1,2
The
importance of these pharmacodynamic effects within the
brain with respect to drug-taking behaviour has been
clearly demonstrated in animal models. For example, psy-
chostimulants are self-administered to a lesser extent in an-
imals in which lesions of the mesolimbic dopamine path-
way have been produced by the application of a selective
neurotoxin or when pretreated with dopamine receptor
blockers.
2
Furthermore, mice that have been bred to have
no dopamine transporter (known as DAT knockout mice)
are unresponsive to the stimulant effects of amphetamine
and cocaine.
28
These mice also fail to show elevations in ex-
tracellular dopamine levels following psychostimulant ad-
ministration, clearly demonstrating the importance of the
dopamine transporter in mediating the effects of the psy-
chostimulants.
Although research in humans is more limited, the find-
ings confirm that similar pharmacodynamic effects occur
following psychostimulant administration in humans.
29
Imaging studies have demonstrated that subcortical re-
gions within the extended amygdala are activated both fol-
lowing cocaine infusion
30
and in response to cue-induced
cocaine craving.
31
Research using positron emission to-
mography imaging techniques has shown that the rein-
forcing effects of psychostimulants are correlated with in-
creases in dopamine concentrations in limbic regions due
to blockade of the dopamine transporter and occupancy of
dopamine D
2
receptors.
32,33
Chronic psychostimulant use
has been shown to cause long-term changes in the func-
tion of the dopamine transporter
34,35
and in D
2
receptor
levels, which may contribute to further psychostimulant
abuse. Despite the extensive evidence for a primary role
for the dopaminergic system in the stimulus–reward prop-
erties of cocaine and amphetamines, clinical trials of
agents that modify dopamine release or block its receptors
have been disappointing.
36
More recently, however, a criti-
cal role for selective dopamine receptor subtypes (e.g., D
1
receptors) in the self-administration and conditioned re-
sponses to cocaine suggests that agents directed at this re-
ceptor may be effective.
37,38
Opiates
Opiate drugs, such as morphine and codeine, are com-
monly used in the clinical setting for pain relief. However,
this class of psychoactive agent can also elicit intense eu-
phoric effects followed by feelings of well-being in the user
when taken in high doses, which can lead to their abuse and
ultimately may result in addiction. Animal research sug-
gests that, as with the psychostimulants, opiates appear to
mediate their reinforcing effects by modulating the activity
of the mesolimbic pathway, although not directly.
39
The
opiates enhance NAcc dopamine release by increasing the
activity of VTA dopamine neurons. It is postulated that this
is achieved via activation of mu-opioid receptors located on
GABA neurons within the VTA, which play an important
role in regulating the activity of VTA dopamine neurons.
Opiates also have dopamine-independent effects within the
NAcc, which play an important role in opiate reward.
40
Evi-
dence supporting these proposed mechanisms of action in-
cludes the observation that morphine and heroin self-
administration can be modified by specifically blocking the
actions of GABA in the VTA and opioid receptors in the
NAcc.
Functional neuroimaging in opiate addicts confirms that
heroin administration and heroin-related cues activate the
same neural systems identified in preclinical animal
studies,
41
providing evidence that these systems modulate
the direct and conditioned pharmacological effects of the
drug. The latter effects are an important element of drug
craving. In addition, pharmacological challenges with drugs
interacting with dopamine receptors have demonstrated
that the activity of brain dopaminergic systems has been al-
tered by long-term opiate use in heroin addicts,
42
and these
changes are proposed to be related to the neural processes
leading to abuse and dependence. The treatment strategies
for opiate dependence using pharmacological agents have
involved 3 different approaches. The most common strat-
egy employed is a harm reduction approach by substituting
less harmful long-acting, orally active opioid agonists for
the more harmful abused substance (e.g., methadone and
buprenorphine maintenance programs).
43,44
Another ap-
proach has been to alleviate symptoms resulting from acute
withdrawal (e.g., using clonidine), which has proved suc-
cessful for facilitating detoxification.
45
A final treatment
strategy has been to block the pharmacological conse-
quences of further opiate use following detoxification by
administering an opioid blocker (e.g., naltrexone). How-
ever, clinical trials suggest that this approach is mainly ac-
ceptable to relatively opiate-free addicts who are highly
motivated for change.
46
Conclusion
The identification of the underlying biological mecha-
nisms of drug dependence has lead to targeted drug devel-
opment. In the case of alcohol, both the opioid and
NMDA systems have been targeted and have resulted in
marketed products, namely, naltrexone and acamprosate
respectively. On the other hand, the discovery that bupro-
pion is effective in treating tobacco dependence was clinical
serendipity. This will, however, probably lead to the recog-
nition of a new contributing neurochemical basis for nico-
tine dependence. Perhaps it is most surprising that there
are no effective pharmacological interventions for cocaine
or stimulant abuse despite our extensive knowledge about
Tomkins and Sellers
820
JAMC • 20 MARS 2001; 164 (6)
how they exert their effects in the brain. This may be a re-
flection of the fact that these substances cause long-term
and often permanent changes in the brain. Current re-
search efforts are now also focusing on exploring the neu-
robiological factors that may underlie relapse into drug-
taking behaviour. This is an important issue because a
successful treatment strategy should be effective in prevent-
ing relapse, which occurs with high prevalence in most
drug- and alcohol-abusing populations.
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Addiction and the brain
CMAJ • MAR. 20, 2001; 164 (6)
821
Competing interests: None declared.
Contributors: Dr. Tomkins is the principal author of this review. Dr. Sellers also
participated in the writing and drafted the original figures.
Reprint requests to: Dr. Denise M. Tomkins, Centre for Addiction
and Mental Health, 33 Russell St., Toronto ON M5S 2S1;
fax 416 595-6922; denise_tomkins@camh.net
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