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The addictive nature of nicotine remains a global health
epidemic. Over three million smoking-related deaths
are reported annually, worldwide. In the Western world,
illness related to smoking is believed to be the cause of
20% of all deaths, making nicotine addiction the single
largest cause of preventable mortality
1,2
. Despite these
grim statistics, tobacco use is increasing in many devel-
oping countries
3
, with smoking-related mortalities
predicted to exceed 10 million per year over the coming
3040 years
1
. Although nicotine is generally not classi-
fied among harder addictive drugs, such as cocaine
or heroin, with continued use tobacco often becomes as
difficult to abandon. As anybody who has ever struggled
with repeated attempts at smoking cessation can attest
to, nicotine is exceptionally intractable to quitting
interventions.
Since the identification of nicotine as the primary
psychoactive component of tobacco smoke, a great
amount of research has been undertaken to unravel the
neuropharmacological, anatomical and behavioural
underpinnings of its psychoactive effects. Various
neural pathways and transmitter systems have emerged
as compelling candidates for the processing of the
psychoactive and addictive properties of nicotine.
Here, we will examine research that implicates specific
neurotransmitter systems, the potential roles of specific
neuronal nicotinic acetylcholine receptor (nAChR)
subtypes and specific neuroanatomical regions that
have been implicated in mediating the addictive prop-
erties of nicotine. In particular, we will review the con-
siderable body of evidence that implicates dopamine
(DA) and non-DA neuronal substrates in the ventral
tegmental area (VTA) as crucial for the rewarding and
aversive motivational properties of nicotine. Whereas
previous research has implicated DA-mediated neuro-
transmission as a direct mediator of a nicotine reward
signal
47
, more recent evidence points to a more com-
plex role for DA systems in the motivational effects of
nicotine, including the aversive effects of nicotine and
drug-induced plastic changes at the synapse
810
.
We propose an integrated model that might account
for the vulnerability to the rewarding and addictive
properties of nicotine through acute actions on non-
DA reward pathways. With continued nicotine expo-
sure, plastic molecular alterations in central DA
systems might underlie the continued propensity to
consume nicotine by inducing craving, the aversive
effects of withdrawal, and aberrant incentive-salience
attribution to environmental stimuli that are associated
with nicotine.
THE NEUROBIOLOGY OF NICOTINE
ADDICTION: BRIDGING THE GAP
FROM MOLECULES TO BEHAVIOUR
Steven R. Laviolette and Derek van der Kooy
Nicotine, the primary psychoactive component of tobacco smoke, produces diverse
neurophysiological, motivational and behavioural effects through several brain regions and
neurochemical pathways. Recent research in the fields of behavioural pharmacology, genetics
and electrophysiology is providing an increasingly integrated picture of how the brain processes
the motivational effects of nicotine. The emerging characterization of separate dopamine- and
GABA (!-aminobutyric acid)-dependent neural systems within the ventral tegmental area (VTA),
which can mediate the acute aversive and rewarding psychological effects of nicotine, is
providing new insights into how functional interactions between these systems might determine
vulnerability to nicotine use.
Neurobiology Research
Group, Department of
Anatomy and Cell Biology,
University of Toronto,
Toronto, Canada,
M5S 1A8, USA.
email:
laviolette@bns.pitt.edu
doi:10.1038/nrn1298
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R E V I E WS
signalling properties of nicotine in various CNS regions.
In particular, studies on the actions of nicotine on DA
pathways, specifically within the VTA, have provided
insights into how nicotine might modify signalling
through DA and non-DA VTA systems.
The VTA and its input and output pathways. The mam-
malian VTA is a midbrain region that has been implicated
in the rewarding motivational effects of a wide variety of
addictive drugs, including cocaine
19
, alcohol
20
, opiates
21,22
and nicotine
8,23,24
. Much evidence implicates the VTA and
its associated efferent and afferent projections as an inte-
grative centre for the psychoactive effects of nicotine.
Within the VTA, DA neurons (designated as the A10 DA
group), and their associated ascending projections to
the nucleus accumbens and prefrontal cortex (PFC),
comprise the well-characterized mesolimbic and meso-
cortical pathways. In addition, a population of VTA
GABA neurons provide inhibitory input to the A10 DA
neurons
25
, and there is anatomical evidence for descend-
ing projections to the brainstem mesopontine region,
including the tegmental pedunculopontine nucleus
(TPP)
26,27
a brain region that is important in DA-
independent reward signalling. Both of these neuronal
populations the DA and GABA neurons are
involved in signalling reward
19,21,28,29
. The VTA also
receives excitatory glutamatergic and cholinergic projec-
tions from both the TPP and the adjacent laterodorsal
tegmental nucleus (LDT)
25,30
, as well as inhibitory GABA
inputs from the TPP
31
. In FIG. 2, the ascending anatomical
DA projections from the VTA to the nucleus accumbens
and prefrontal cortex, as well as the VTAs GABA connec-
tions with the TPP are shown. Recent electrophysiological
work onbrain slices has provided insights into the cellular
mechanisms by which nicotine interacts with both of
these neuronal populations in the VTA, and has impli-
cated the VTA as a crucial site for central nicotine sig-
nalling through several pre- and postsynaptic substrates.
Neurophysiology of nicotine signalling in the VTA.
Neurons within the VTA have a wide variety of nAChRs
17
,
and nicotine can activate both the DA and GABA neu-
rons of the VTA
32,33
. The nAChR receptor profiles that
are associated with these DA and GABA neurons differ
considerably, and these differences might have important
functional consequences for nicotine signalling in the
mesolimbic system. For example, DA neurons of the
VTA express the "2"7 and #2#4 subunits
34,35
, which
can give rise to at least three pharmacologically distinct
nAChR subtypes, of which one is probably a homomeric
"7 receptor. Although less than half of the VTA neurons
express nAChRs that contain "7 (REF. 17), this subunit is
preferentially localized within the midbrain in the VTA,
relative to the adjacent substantia nigra
17
. By contrast, less
than 25% of the GABA neurons express the "3, "5, "6
and #4 subunits
35
, indicating that most nAChRs of these
VTA neurons contain the "4 and #2 subunits.
The administration of nicotine within concentration
ranges that are readily self-administered in rodents and
humans has been shown to increase DA release in
the nucleus accumbens
24,36
. Furthermore, within the
Nicotine signalling: pharmacology and anatomy
Nicotine acts on endogenous nAChRs that are found
ubiquitously throughout the central (CNS) and periph-
eral nervous systems in almost all vertebrate and inver-
tebrate species. The nAChRs are pentameric receptor
complexes that serve as ligand-gated ion channels (FIG. 1).
So far, 12 different neuronal nAChR subunits have been
identified: "2"10 and #2#4 (REFS 1115). The nAChR
receptors form different combinations of "- and
#-subunits. However, the "7"9 subunits can also form
homomeric nAChRs
16,17
.
Functionally, the nAChR receptor complex can exist
in three conformational states, which are dynamically
regulated by exposure to the agonist: closed, open and
desensitized
11
. When agonists bind to the nAChR, the
receptor complex undergoes a conformational change
in its structure, which allows the channel gate to open,
permitting the passage of cations (such as Na
+
, K
+
and
also Ca
2+
, which might account for 110% of the nAChR-
mediated current
18
) through the channel pore.
Ligand binding can produce a diverse range of neuro-
physiological effects. For example, nAChRs made of
different subunit combinations can be located either on
the soma and/or neuronal processes, enabling nAChR to
act at the cell body and at the presynaptic and postsynap-
tic regions (FIG. 1). In vitro studies have examined the
COOH
M1 M2 M3 M4
a
b
NH
2
H
2
N
H
2
N
HOOC COOH
Extracellular
Cytoplasmic
Ligand binding site
Preterminal
nAChRs
Presynaptic
nAChRs
Postsynaptic
nAChRs
Figure 1 | The structure of neuronal nicotinic acetylcholine receptors (nAChRs).
a | Although the precise molecular structure of nAChRs is not known, they are believed to be
pentameric ion channels. Each nAChR is composed of five subunits arranged in either homomeric
or heteromeric complexes of "- or #-subunit arrangements (left). Different subunit combinations
confer unique functional properties to the ubiquitously distributed nAChRs throughout the brain.
The schematic on the right shows the transmembrane topology of a single nAChR subunit. The
transmembrane domains are labelled M1M4. The larger amino-terminal domain contains the
acetylcholine-binding site, whereas the M2 domain determines the ionic selectivity of the receptor
and faces the inside of the channel pore. b | nAChRs are located at the soma, on presynaptic
terminals and on postsynaptic boutons. This widespread localization confers the receptor with a
wide range of functions, influencing neuronal signalling at the pre- and postsynaptic levels.
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R E V I E WS
activity of both DA and GABA neurons, leading to inter-
esting findings about how nicotine affects the functional
relationship between these two neuronal groups.
Whereas the early, acute effects of nicotine in the VTA
predominantly affect GABA neurons, the nAChRs
that are associated with these cells desensitize rapidly
9,33
,
leading to a long-lasting excitation of the DA neurons
through removal of the inhibitory influence of GABA. In
addition, the desensitization of inhibitory inputs to the
DA system correlates with enhanced glutamatergic input
to the DA neurons through the actions of nicotine on
presynaptic nAChRs that are located on VTA glutamater-
gic terminals, which show a lesser degree of desensitiza-
tion after nicotine exposure
33
. Extracellular recordings of
DA neurons of the VTA in vivo after intravenous nicotine
administration lead to a similar conclusion; nicotine can
modify the activity of DA neurons through its actions on
inhibitory GABA neurons
40
.
Functionally, nicotine activation of GABA neurons
would be expected to initially increase inhibitory input
to the DA neurons (FIG. 2). However, with continued
exposure to nicotine and the subsequent desensitization
of the nAChRs of the GABA neurons, nicotine would
presumably bypass these inhibitory cells and act directly
on the DA neurons. These findings
32,33,40
indicate
that there might be a net shift in the activity level of DA
neurons relative to the GABA cells in the VTA (FIG. 2)
after prolonged in vitro or in vivo exposure to nicotine at
concentrations that are comparable to those observed in
the plasma of smokers. This shift would favour increased
activity of the mesolimbic DA pathway. Although future
studies are required to clarify these issues, the differences
in desensitization kinetics between the distinct nAChR
subunits and their divergent expression patterns on DA
and GABA neurons in the VTA might account for the
functional differences between these cells in response to
nicotine exposure.
In addition to the actions of nicotine on DA and
GABA neurons, considerable evidence indicates that the
actions of nicotine within the VTA might be mediated by
glutamatergic transmission. Anatomically, the VTA
receives substantial glutamatergic inputs from cortical
and subcortical structures
25
. These excitatory inputs
synapse on DA and GABA neurons
25,30
(FIG. 2), and can
therefore modulate the activity of both cell types. Various
studies have indicated that "7-containing nAChRs might
have a specific role in mediating the presynaptic actions
of nicotine in the CNS, and, in particular, might regulate
the release of glutamate
41,42
. Systemic nicotine has been
shown to elevate glutamate levels in the VTA, and this
effect is blocked by the relatively selective "7-subunit
antagonist methyllycaconitine (MLA)
43
. In addition,
lesions of the prefrontal cortex a region that provides
glutamatergic inputs to the VTA reduce binding of the
nAChR antagonist "-bungarotoxin in the VTA. This
observation provides further evidence for the presynaptic
localization of "7-containing nAChRs in the VTA,
presumably in glutamatergic terminals
43
.
Blockade of NMDA (N-methyl-D-aspartate) receptors
and "7-containing nAChRs in the VTA diminishes the
increase in mesolimbic DA release that is induced by
physiological range of plasma nicotine concentrations
that are obtained by smokers (~0.5 M)
37
, nicotine
potently activates DA neurons of the VTA
37
, an activation
that is followed by desensitization of nAChRs after con-
tinued exposure to nicotine
37
. This observation indicates
that, whereas the acute excitatory action of nicotine on
DA neurons might signal its reinforcing, rewarding effect,
the long-lasting desensitization of VTA nAChRs might
represent a cellular basis of nicotine tolerance. Such a
characterization seems reasonable, given the anecdotal
reports that smokers tend to enjoy most the first cigarette
of the day (at a time when nAChRs would not be in a
state of prolonged desensitization). However, activation
of DA neurons is not a scalar index of reward, nor is the
corresponding increase in DA release in the target regions
of the mesolimbic system a simple reinforcement signal
(see later in text)
38,39
. As we will discuss, mesolimbic DA
signalling also mediates aversive motivational events
33
and is involved in associative learning processes
38,39
.
Because of the important functional relationship
between the DA and GABA neurons in the VTA
25
(FIG. 2),
it is imperative to examine the effects of nicotine on both
of these neuronal populations. Recent studies on VTA
slices have investigated the actions of nicotine on the
b
a
TPP
VTA
Nucleus
accumbens
GABA
Glutamate
inputs
PFC
NAc
VTA
TPP
Dopamine
Figure 2 | The ventral tegmental area (VTA), and its efferent and afferent systems.
a | Human (left) and rat (right) brains, showing the mesolimbic and mesocortical dopamine (DA)
pathways, which originate in the VTA and send ascending projections to the nucleus accumbens
(NAc) and prefrontal cortex (PFC), respectively. These pathways are strongly activated by nicotine
and are implicated in its rewarding and aversive psychological properties. The VTA also sends a
descending projection to the tegmental pedunculopontine nucleus (TPP), a brain region that is
involved in non-DA-mediated reward signalling. The rewarding effects of nicotine are blocked by
lesions
69
or GABA (!-aminobutyric acid)-mediated inhibition
78
of this nucleus. Ascending
cholinergic and glutamatergic projections from the TPP also influence VTA neuronal activity and
can regulate the activity of DA neurons in the VTA
46,47
. b | Schematic showing the DA and GABA
neuronal populations within the VTA. GABA neurons send descending projections to the TPP and
provide inhibitory input to DA neurons. Both neuronal populations are activated by nicotine
32,33,40
.
In addition, both neuronal populations receive excitatory glutamatergic inputs, which can regulate
the relative activity of DA and GABA activity in the VTA.
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addiction is the delineation of the neuronal mechanisms
that might be involved in transmitting the rewarding and
aversive motivational effects of nicotine. Understanding
how these neural systems interact might yield important
clues as to how the brain initially responds to acute nico-
tine exposure (as a rewarding or an aversive stimulus),
and how the continued exposure to the drug might even-
tually lead to dependence (compulsive nicotine craving
and withdrawal symptoms).
Defining the role of DA: reward or aversion? For many
years, a common theme in the literature on behavioural
neuropharmacology has been the hypothesis that
DA and its associated neural pathways serve as specific
transducers of central reward signals. In its most
simplistic form, this view of DA implies that any drug or
stimulus that can produce reward as measured by behav-
ioural reinforcement tests, such as conditioned place
preference (CPP) or intravenous self-administration
of the drug (BOX 1), does so by increasing levels
of DA through activation of the mesolimbic pathway
61
.
In this sense, DA was considered a direct, scalar index
of reward. However, recent research has called into ques-
tion this conceptualization of DA in motivational sig-
nalling, particularly in light of the fact that DA signalling
also correlates with aversive, noxious stimuli
38,39
, and
might serve to signal conditioned stimuli that predict
reward (or errors in reward prediction), rather than the
rewarding events per se
62
. A role for DA-mediated trans-
mission in such cognitive processes might transcend
drug-naive versus drug-dependent states and might be
relevant for motivationally important learning
processes, independent of their rewarding or aversive
emotional valence. However, a large body of research
has supported the idea that the rewarding effects of
several psychoactive drugs, including nicotine, are
dependent on mesolimbic DA-mediated transmission.
Indeed, DA neural systems have arguably received the
greatest amount of experimental attention as potential
mediators of the rewarding effects of nicotine.
Using an intravenous procedure for the self-
administration of nicotine, several studies have reported
that blocking DA-mediated transmission, pharmacolog-
ically or by lesions of the mesolimbic DA pathway, is suf-
ficient to reduce or completely block the reinforcing
effects of nicotine. For example, Corrigall et al.
4
showed
that pretreatment with specific antagonists of D1 or D2
DA receptor subtypes strongly attenuated nicotine self-
administration. Lesions of the mesolimbic DA system
caused by 6-hydroxydopamine, a molecule that selec-
tively destroys DA neurons, also attenuate nicotine
self-administration
5
. Similarly, microinfusions of the
nAChR antagonist dihydro-#-erythroidine directly into
the VTA attenuate nicotine self-administration, but not
the reinforcing effects of food or cocaine, implicating
that the mesolimbic DA projection from the VTA is a
crucial mediator of the reinforcing effects of nicotine
6
.
Work using gene knockout technology has further
implicated mesolimbic DA-mediated transmission in
nicotine reward. Elimination of specific nAChR sub-
units has shown that the nAChR subunits that are
nicotine
44
. This apparently unique role for the "7 subunit
in the VTA might have important implications for the
psychoactive effects of nicotine. Indeed, as we will discuss,
various studies have indicated that functional interactions
between DA, GABA and glutamate within the VTA
are vital for the mediation of the motivational properties
of nicotine.
Cholinergic modulation of DA function in the VTA
through brainstem projections. The functional connec-
tions between the brainstem nuclei TPP and LDT with
the VTA have been studied extensively (FIG. 2). Ascending
inputs from the TPP and LDT to the VTA comprise
cholinergic and glutamatergic fibres that synapse on DA
and GABA neuronal populations of the VTA
30
. The
cholinergic neurons of the TPP and LDT have been
termed the Ch5 and Ch6 cell groups, respectively
45
, and
these inputs can modulate the activity of the mesolimbic
DA system. For example, electrical stimulation of the TPP
elicits striatal DA efflux as measured by MICRODIALYSIS
46
,
whereas LDT stimulation elicits a similar DA efflux in the
nucleus accumbens through the activation of cholinergic
and glutamatergic receptors in the VTA
47
.
The behavioural effects of these ascending cholinergic
inputs to the VTA seem to depend more importantly on
signalling through muscarinic acetylcholine receptors
than through nAChRs. For example, ANTISENSE KNOCKDOWN
of muscarinic M5 receptors in the VTA of rats reduces
the rewarding efficacy of stimulating the MEDIAL FOREBRAIN
BUNDLE
48
. Similarly, pharmacological blockade of
muscarinic receptors in the VTA is more effective than
blockade of nAChRs at attenuating the rewarding effects
of this stimulation
49
. These in vivo findings point to
the behavioural complexity of cholinergic signalling
in the VTA. Indeed, the functional balance between
DA and GABA VTA neuronal substrates might have
important implications for the central processing of the
motivational properties of nicotine.
The dual motivational effects of nicotine
We tend to think about drugs of abuse in terms of their
ability to produce feelings of pleasure. Indeed, nicotine is
known to induce feelings of pleasure and reward in
humans and other species. But like many other addictive
drugs, nicotine also has potent, aversive, unpleasant
effects
5052
. Nicotine can produce powerful anxiogenic
effects systemically and centrally
53,54
through activation of
nAChR that contain "4, "7 or #2 subunits
55
. Many peo-
ple experience noxious effects such as nausea, coughs and
dizziness on their initial experience with tobacco
56,57
.
Interestingly, tolerance to the aversive effects of nicotine
develops with repeated exposure
52,58
. Although the precise
neurobiological mechanism that underlies this tolerance
to nicotine aversion is unknown, its existence indicates
that chronic nicotine exposure might induce a functional
alteration in neural systems that mediate the aversive
and/or rewarding effects of nicotine.
It has been suggested that relative sensitivity to the
rewarding or aversive properties of nicotine might serve
as a predictor of who might become addicted to
tobacco
59,60
. So, an important goal in the study of nicotine
MICRODIALYSIS
A technique that allows the
sampling of neurochemicals in
the brain of live animals.
It commonly uses a small
U-shaped cannula that serves a
dual function: it allows the
injection of molecules of interest
to test their effect, and it
provides a pathway for the flow
and subsequent collection of
perfusate from a small brain
area.
ANTISENSE KNOCKDOWN
Oligonucleotides with a
sequence that is complementary
to the mRNA of a given
molecule can be used to block its
translation. The subsequent
temporary elimination of the
protein of interest often provides
useful information on its
biological function.
MEDIAL FOREBRAIN BUNDLE
Complex fibre tract that runs
through the diencephalon. It
contains descending fibres from
telencephalic structures such as
the basal olfactory regions, the
periamygdaloid region and the
septal nuclei, and ascending
fibres from the aminergic
brainstem nuclei. Intracranial
stimulation along this tract can
simulate motivational states and
reinforce behaviour.
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Box 1 | Tasks used to study the motivational properties of nicotine
A behavioural test that is commonly used to study the
motivational properties of nicotine and other drugs is
conditioned place preference (CPP; a). In this
procedure, animals receive a specific drug and are
placed in a unique environment that has a specific
odour, colour and/or texture. On the next day, the
animal receives the vehicle instead of the drug and is
placed in another conditioning environment. After
several such cycles, animals are given the opportunity
to spend time in either the environment previously
paired with the drug or with the vehicle. A key
advantage of this task is that the experimenter controls
the precise amount and time course of exposure to the
drug in question. More importantly, CPP allows the
testing of both the rewarding properties of a drug (the
animal can show a preference for the previously drug-
paired environment) and its aversive properties (the
animal can actively avoid an environment previously
paired with the drug). An important drawback of CPP
is that drugs are passively administered by the
experimenter, instead of being self-administered, as is
the case for real-life drug-taking behaviour. However, the associative learning that takes place during the CPP task
might resemble the strong associations that smokers develop between the environmental cues that are associated with
smoking and the reinforcing effects of nicotine
111
.
Another commonly used model is the intravenous self-administration of drugs (b). Animals can be trained to
reliably press a lever to receive a discrete infusion of drug. Lesions to specific brain regions or pre-treatments with
specific pharmacological agents, such as dopamine (DA) receptor antagonists, can be performed to examine their
effects on self-administration. This model has been successfully used to measure nicotine reinforcement in rodents and
primates
50
. One of the primary advantages of the self-administration model is its resemblance to real-life drug-taking
behaviour in humans: just like human smokers, animals trained in this task will consistently and compulsively self-
administer nicotine
50
. The lever presses are termed operant responses. Most studies on nicotine reinforcement rely on
a fixed-ratio schedule of operant responding in which the animal must make a fixed number of bar presses to receive a
single infusion of nicotine.
A third task that is used in studies on the motivational effects of nicotine is conditioned taste aversion (CTA; c). CTA is
believed to tap directly into the aversive properties of a drug by taking advantage of the fact that animals seem
intrinsically able to associate specific tastes with aversive states. By pairing a specific drug with a particular taste, animals
might learn to avoid such a taste, as the unpleasant effects of the drug become associated with it. By contrast, a taste that is
paired with the injection of vehicle is not avoided when the animal is given a choice between the two tastes. Many studies
have used nicotine as a drug stimulus in this task and have reported that, like many other addictive drugs, it produces
potent aversive effects
8,10,50
. Such reports, in combination with studies using the self-administration or CPP procedures,
have conclusively shown the dual nature of the motivational effects of nicotine in animals, consistent with the reported
aversive and rewarding psychological effects of nicotine in humans.
Drug
Drug
a
b
c
Choice
Choice
Vehicle
Vehicle
?
?
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nicotine
51
, or no apparent motivational effects at all
64
. But
a limitation of these studies is that they relied exclusively
on systemic nicotine administration, which also targeted
peripheral nAChRs. The activation of these receptors
could potentially produce toxic and noxious effects, lead-
ing to the expression of such a conditioned place aversion.
Intravenous nicotine self-administration also activates
peripheral nAChRs, and high concentrations of intra-
venously administered nicotine do produce aversive
effects
50
.
An early study reported that infusions of the nicotinic
agonist cytisine directly in the VTA to exclude peripheral
effects could produce reward as measured in the CPP
test
65
. A more recent study reported that both rewarding
and aversive effects could be measured using the same
test after microinfusions of nicotine itself into the VTA
8
.
This study reported a dose-dependent, biphasic curve for
the motivational effects of nicotine in the CNS; whereas
a lower nicotine concentration in the VTA produced
an aversive effect, higher concentrations produced
potent rewarding effects (FIG. 3c). So, within a single brain
region, nicotine can have rewarding or aversive effects as
a function of nicotine concentration.
Surprisingly, when the rewarding effects of higher
nicotine concentrations were challenged by blocking
DA-mediated transmission, either systemically or directly
in the nucleus accumbens, there was no attenuation of the
rewarding effects of nicotine. However, under these
conditions, levels of nicotine in the VTA that previously
produced no motivational effects now had rewarding
effects, whereas the effects of lower nicotine concentra-
tions switched from aversive to rewarding (FIG. 3d). In
addition, when the aversive effects of nicotine were exam-
ined in the CTA test, DA receptor blockade prevented the
aversive nicotine signal
8
. So, by contrast to previous stud-
ies of intravenous nicotine self-administration, these
studies have indicated that the rewarding and aversive
effects of nicotine are mediated within the VTA by sepa-
rate and dissociable systems. Whereas the acute rewarding
properties of nicotine were independent of DA signalling,
the aversive effects of nicotine were crucially dependent
on DA-mediated transmission
8
.
Although these results from the CPP model point
to an opposing functional role for DA signalling in the
motivational effects of nicotine within the VTA, there
are crucial differences between the CPP and the self-
administration studies. The most important of these
differences is that in studies of self-administration
46,63
the
animals receive chronic exposure to nicotine, often over
several weeks. By contrast, in most CPP studies, animals
are naive to nicotine at the beginning of the experiment,
and the drug is passively administered by the experi-
menter in controlled doses (BOX 1). So, whereas DA recep-
tor blockade seems to attenuate nicotine reinforcement in
animals that are chronically exposed to nicotine, the acute
rewarding effects of nicotine can be mediated through a
non-DA system in the VTA. In addition, when the acute
aversive effects of nicotine are blocked by interfering with
mesolimbic DA receptor signalling, the rewarding effects
of nicotine are potentiated, presumably by the removal of
an aversive signal
8
. As we will discuss, the motivational
required for nicotine-induced DA release are also neces-
sary for nicotine self-administration
7,63
. For example,
mice that lack the #2 nAChR subunit showed decreased
DA release in response to nicotine exposure, and this
effect correlated with a strong attenuation of nicotine
self-administration
63
, indicating that the ability of this
subunit to produce nicotine reward might be tightly
linked to its functional regulation of DA release in the
mesolimbic pathway (FIG. 3a,b). Interestingly, these
mutant mice also showed a strong reduction in nicotine-
induced conditioned taste aversion (CTA)
10
(BOX 1), indi-
cating that a specific nAChR subunit that is linked to
mesolimbic DA-mediated transmission is also involved
in the aversive effects of nicotine. But studies using CPP, a
test that is sensitive to both the aversive and rewarding
properties of drugs, have disclosed a far more complex
role for DA in the motivational properties of nicotine.
A common neural substrate for nicotine reward and
aversion. Many early studies on the motivational effects
of nicotine using the CPP test reported that, rather
then producing a rewarding effect, nicotine produced
aversive effects, as manifest by the development of
conditioned aversions to environments paired with
*
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WT nicotine
nAChR#2
/
WT saline
Neuroleptic
Control
Cocaine
Preference (+)
Aversion ()
Preference (+)
Aversion ()
Cocaine
Naive Naive
a b
c d
Figure 3 | Different roles for dopamine (DA) signalling in the acute versus chronic phases of
nicotine exposure. a | Nicotine self-administration is significantly attenuated in mice lacking the
nicotinic acetylcholine receptor (nAChR) subunit #2 (nAChR#2
/
), relative to wild-type (WT) animals.
b | This attenuation is specific to nicotine, as the reinforcing effects of cocaine are unaffected in these
mutant animals. Elimination of the nAChR #2 subunit also attenuates nicotine-induced DA release
63
,
indicating that DA signalling might be essential for nicotine reinforcement. Reproduced, with
permission, from Nature REF. 63 $(1998) Macmillan Magazines Ltd. c | By contrast, the acute effects
of nicotine produce biphasic motivational effects within the VTA. Whereas a low nicotine
concentration produces aversion (as measured in the conditioned place preference task), high
concentrations produce potent rewarding effects. d | Blockade of DA signalling with a systemic
neuroleptic drug ("-flupenthixol) does not block the rewarding effects of high nicotine concentrations,
potentiates the rewarding effects of middle-range nicotine doses, and switches the motivational
effects of a low concentration from aversive to rewarding. Reproduced, with permission, from REF. 8
$(2003) Macmillan Magazines Ltd. Asterisks in a and bindicate P<0.05.
2004 Nature PublishingGroup
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R E V I E WS
neurons
75
. In addition, intracranial self-stimulation
activates GABA neurons of the TPP, rather than the
cholinergic Ch6 cells
76
, further indicating that non-
cholinergic TPP mechanisms might be involved in
reward signalling.
Together, this evidence indicates that descending VTA
inputs to the TPP might be the primary transducers of
the nicotine reward signal. For example, bilateral excito-
toxic lesions of the TPP block nicotine reward in the
VTA and switch the motivational valence of nicotine
from rewarding to aversive, as measured in the CPP
model
69
. This result indicates that, whereas the TPP
seems to selectively mediate a nicotine reward signal, the
aversive effects of nicotine in the VTA (which are depen-
dent on DA-mediated transmission in the acute state)
remain intact after removal of the TPP pathway. An early
report found that partial lesions of the dorsal TPP did
not affect nicotine self-administration
6
, but a subsequent
report from the same group claimed that more extensive
and localized TPP lesions strongly attenuated nicotine
self-administration
77
. Within the TPP, GABA receptors
seem to be crucial for transmission of a nicotine
reward signal. Corrigall et al.
78
reported that GABA
A
and
GABA
B
receptor agonists that were infused into the
TPP attenuated nicotine self-administration on a fixed-
ratio schedule of operant responding (see BOX 1). In
addition, infusions of nicotine into the TPP induce CPP,
further implicating the TPP as a non-DA system that is
important for the motivational effects of nicotine
79
.
So, increasing evidence indicates that non-DA neural
substrates, including a GABA-mediated system within
the TPP, might be important for the reinforcing and
addictive properties of nicotine. Future studies are
required to map out the functional pathways from the
VTA to these non-DA neuronal reward substrates.
Emerging roles for the "7 subunit and glutamate. As
described previously, "7-containing nAChRs might be
preferentially involved in the regulation of the presynap-
tic effects of nicotine on glutamate release
4143
. Such a role
for the "7 subunit has been shown in various brain
regions, including the VTA
4143
. Until recently, no direct
behavioural evidence had linked this particular subunit
to the motivational effects of nicotine. However, several
reports now indicate that "7 might be preferentially
involved in the acute rewarding effects of nicotine.
Panagis et al.
80
reported that direct microinfusions of
MLA in the VTA attenuated nicotine-induced potentia-
tion of reward in an intracranial self-stimulation experi-
ment. However, Grottick et al.
81
found that blockade of
"7-containing receptors had no effect on intravenous
nicotine self-administration in animals chronically
treated with nicotine, nor on the hyperlocomotor effects
of chronic nicotine exposure, indicating that "7 might
not be involved in the motivational signalling of nicotine
after chronic exposure. Similarly, a recent study using
MLA over a wide concentration range found that this
antagonist blocked the acute effects of nicotine adminis-
tered directly into the VTA, and switched its motivational
valence from rewarding to aversive
82
. By contrast, #2-
containing nAChRs are implicated in both the rewarding
state drug-naive, drug-dependent or withdrawn
might be vital to determine the role of DA in nicotine
addiction.
Beyond DA: new players in nicotine addiction
As DA does not exclusively transmit a nicotine reward
signal, what other substrates are involved in the addictive
properties of nicotine? As previously noted, nicotine pro-
duces the physiological activation of both DA and GABA
neurons in the VTA
32,33,40
. As GABA neurons serve as a
substrate for non-DA-mediated reward transmission
28,29
and are acutely activated by nicotine
32,33,40
, this neuronal
population is a good candidate for the mediation of nico-
tine reward signalling in the VTA. A recent report has
found that GABA receptors in the VTA might be impor-
tant mediators of the reinforcing properties of nicotine.
Corrigall et al.
23
reported that direct microinfusions of
GABA
A
or GABA
B
receptor agonists into the VTA caused
a significant reduction in nicotine self-administration,
indicating that GABA receptors in the VTA can also
mediate nicotine reinforcement. Whereas GABA
A
recep-
tors in the VTA are predominantly localized to GABA
neurons
25,28
, GABA
B
receptors are primarily localized on
DA neurons and can strongly modulate the activity of the
mesolimbic DA system
25,66,67
. Activation of GABA
B
recep-
tors in the VTA can strongly decrease mesolimbic DA
activity
66,67
and attenuate nicotine-induced DA release in
the mesolimbic pathway
67,68
. These data are consistent
with a role for GABA
B
receptors in the control of VTA
DA neurons. These results are also consistent with obser-
vations in animals that chronically self-administered
nicotine, as blockade of DA signalling or direct inactiva-
tion of the mesolimbic DA system with a GABA
B
receptor
agonist can block nicotine reward in this model.
The TPP. The TPP is crucially involved in the trans-
mission of drug-related
21,69,70
and natural reward
information
70,72
. Notably, the TPP seems to be especially
important in the early, acute phase of drug exposure.
For example, lesions of the TPP block opiate reward, as
measured in the CPP and self-administration tasks, only
during the early stage of drug exposure
21,71
. Although the
TPP has been implicated in the rewarding effects of
opiates
21,70
, food
70
and sex
72
, the rewarding properties
of drugs such as cocaine
73
do not seem to require this
region. In the case of nicotine, several reports have impli-
cated the TPP in the mediation of its rewarding effects.
Anatomically, the TPP and VTA are connected by
descending GABA inputs from the VTA, and by ascend-
ing cholinergic and glutamatergic inputs from the TPP
(FIG. 2). Although these ascending cholinergic inputs from
the TPP to the VTA DA neurons can influence the activity
of the mesolimbic DA system
46,47
, it is unlikely that these
inputs are directly involved in nicotine reward for several
reasons. First, the cholinergic inputs to the VTA are topo-
graphically organized such that most of the cholinergic
brainstem projections to the VTA arise from the adjacent
LDT, rather than from the TPP, which projects more
heavily to the adjacent substantia nigra
74
. Second, acutely
administered nicotine predominantly activates non-
cholinergic TPP cells, including GABA and glutamate
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R E V I E WS
nicotine by determining the relative sensitivity to the
rewarding or aversive psychological effects of nicotine.
But how do alterations in DA signalling during pro-
longed exposure ultimately lead to a role for DA in the
motivational effects of nicotine in the drug-dependent
state? Here, we consider two alternative possibilities.
First, considerable evidence indicates that, rather
than transmitting an acute reward signal during the
early exposure to drugs, DA is specifically involved in
the late phases of the drug-addiction process, and medi-
ates drug craving or wanting. This view, proposed by
Berridge and Robinson
85,86
, states that, after repeated
drug exposure, sensitization of the DA systems, which
signal the INCENTIVE SALIENCE of the drug (that is, how
much the drug is craved), leads to a pathological ampli-
fication of this salience, leading to compulsive drug
seeking and use. Indeed, repeated nicotine exposure
induces sensitization of DA pathways
87,88
and increases
DA receptor expression in the projection areas of the
VTA DA system
89
. In addition, specific blockade of
D3 DA receptors has recently been shown to prevent
nicotine-induced relapse to nicotine-seeking behav-
iours, indicating that alterations of this particular
DA receptor subtype might be specifically involved in
nicotine craving and relapse
90
. However, there is little
evidence to suggest that the sensitized DA-mediated
psychomotor responses to repeated nicotine represent
an enhancement in the rewarding properties of nicotine
per se. In addition, prolonged nicotine exposure might
have profound effects on nAChR expression. Indeed,
many studies have reported that chronic nicotine expo-
sure increases the number of nAChR receptor subtypes
in various brain regions
91
. Although it is not known if
such nAChR receptor upregulation is related to an
increased DA responsiveness after chronic nicotine
exposure, upregulation of "4, #2 and "7 nAChR
subunits
92
within the VTA
93
or other DA systems could
conceivably contribute to such a heightened response.
A related possibility is that plastic processes that
increase DA responsivity to nicotine within the VTA
might represent an aberrant form of drug-induced asso-
ciative learning. Interestingly, exposing humans to
imagery of stimuli that are associated with smoking (and
so with the incentive properties of nicotine) activates
neural regions that are linked to drug-induced DA
sensitization processes, including the prefrontal cortex,
amygdala and orbitofrontal cortex
94
. Although direct
functional comparisons between in vivo behavioural
studies and in vitro neuronal recording studies are tenu-
ous, it is possible that plastic alterations at DA synapses in
the VTA lead to a prolonged activation of DA pathways.
This activation might result in persistent nicotine craving
owing to the pathological amplification of an incentive-
learned association between nicotine and environmental
stimuli that are associated with nicotine exposure (such
as the sight of a cigarette or the smell of tobacco smoke).
Blockade of this DA-mediated incentive learning signal
in animals that are chronically exposed to nicotine would
be expected to reduce nicotine self-administration, as
indeed shown by most self-administration studies
47,63
.
So, once dependence to nicotine has developed after
and aversive effects of nicotine
6,8,10,63
, and seem to block its
reinforcing effects in both the acute and chronic stages of
exposure
6,8,63
. A caveat of these studies is that MLA at
low concentrations interacts with nAChRs that do not
contain the "7 subunit
35
.
Several studies have found that blockade of glutama-
tergic transmission with specific NMDA receptor antago-
nists that are administered systemically or directly in the
VTA can block the rewarding
8284
and aversive
82
effects of
nicotine. Interestingly, blockade of NMDA receptors
is effective in reducing the reinforcing effects of nico-
tine in both the acute and chronic phases of nicotine
exposure
8284
.
An integrated model of nicotine addiction
The complexity of the motivational and physiological
effects of nicotine makes it a formidable task to develop
a unifying model of nicotine addiction. Owing to the
ubiquity of central nAChR distribution, nicotine exerts
multiple effects in many brain regions beyond the VTA.
But as the studies that we reviewed in this article attest
to, the VTA and its associated input and output path-
ways seem to be integral to the transmission of the
motivational properties of nicotine.
By comparing the results of molecular, electrophysi-
ological and behavioural investigations on the central
actions of nicotine, an integrated picture of the nicotine
addiction process is beginning to emerge. A consistent
theme is the dichotomy in the roles of DA in the moti-
vational properties as a function of the stage of nicotine
dependence. Indeed, whereas the rewarding effects of
nicotine within the VTA can be mediated through DA-
independent mechanisms in the early, acute phases of
nicotine exposure
8,69,75
, blockade of DA-mediated trans-
mission seems to attenuate its reinforcing properties
once chronic exposure and dependence have taken
place
46,63
. What mechanism could account for this
apparent shift in the role of DA-mediated transmission
as a function of nicotine exposure? Do the effects of DA
receptor blockade in nicotine-dependent animals inter-
fere with a rewarding effect of nicotine or with some
other psychological process?
FIGURE 4 presents a simplified model that summa-
rizes some of the known functional differences between
the role of DA and non-DA systems of the VTA in rela-
tion to the motivational effects of nicotine in the acute
versus the chronic (addicted) state. We suggest that the
shift from the acute effects of nicotine to the develop-
ment of a dependence state involves a switch in the
functional role of DA signalling in the VTA. In the acute
state, activation of DA neurons by nicotine induces
aversive effects, whereas GABA neurons and the associ-
ated descending inputs to the TPP mediate its rewarding
effects
8,69,75
. Nicotine transiently activates GABA neu-
rons, the nAChRs of which rapidly desensitize
33
.
Simultaneously, nicotine potentiates glutamatergic
transmission through nAChRs that show slower desen-
sitization, leading to a functional shift in the actions of
nicotine from the GABA to the DA neurons
33
. The bal-
ance between these separate systems might determine
the initial vulnerability to the addictive properties of
INCENTIVE SALIENCE
A psychological process whereby
the perception of stimuli is
transformed by increasing their
salience, making them more
attractive or wanted.
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R E V I E WS
behavioural tolerance to nicotine that has been reported
in vivo. Indeed, whereas nAChR desensitization can take
place in the order of seconds to minutes after nicotine
exposure in vitro, behavioural nAChR tolerance in vivo
develops over days or weeks.
Chronic nicotine exposure and withdrawal can induce
profound alterations in the mesolimbic DA system in
rodents
8789,95
and humans
96
. It is possible that chronic
nicotine causes a long-term reduction of the baseline
level of DA-mediated signalling as a compensatory
response after heightened DA-mediated transmission
during continued nicotine exposure. Indeed, medications
that increase DA concentrations have proven efficacious
in preventing nicotine relapse and craving in smokers
97
.
However, DA receptor antagonists and agonists have
been reported to reduce nicotine intake in healthy smok-
ers
98
and in chronic smokers with schizophrenia
99,100
. In
addition, DA receptor agonists and antagonists increase
subjective measures of nicotine craving in chronic smok-
ers
101
. If a lowered level of DA tone were responsible for
the aversive nature of nicotine withdrawal, it seems
unlikely that blocking or activating DA receptors would
increase nicotine intake and subjective measures of crav-
ing. If a lowered baseline level of DA-mediated signalling
were responsible for the aversive effects of nicotine with-
drawal, it might be predicted that blocking DA-mediated
transmission would worsen withdrawal and craving, in
which case animals that self-administer nicotine might be
expected to increase, rather than decrease, their intake.
In addition, several studies have found that chronic
nicotine does not lead to a decreased DA tone in response
to subsequent nicotine exposure
102,103
, but rather to an
enhanced DA release in response to nicotine after chronic
nicotine exposure
104
. NEUROLEPTICS have also been reported
to increase smoking rates in people with schizophrenia;
this effect might represent a potentiation of the reward-
ing properties of nicotine, or a compensatory response
owing to a decrease in such rewarding effects
105
.
The
exceedingly high rates of nicotine addiction that are
observed in people with schizophrenia
106
might indicate
that abnormalities in DA-mediated signalling, which are
considered to be a cardinal underlying pathology of
schizophrenia, might increase the motivational salience
and rewarding effects of nicotine
8,106
.
These findings raise the possibility that by pharmaco-
logically regulating DA-mediated transmission during
nicotine withdrawal, the unpleasant psychological effects
of withdrawal and craving after chronic nicotine expo-
sure might be alleviated. By extension, the ability of DA
receptor blockade to reduce nicotine self-administration
in animals chronically exposed to nicotine might be due
to a blockade of the aversive effects of nicotine with-
drawal. In other words, by blocking the aversive effects of
nicotine withdrawal and craving, self-administration
of nicotine would be reduced. Interestingly, chronic
opiate exposure and withdrawal also alter DA-mediated
signalling
107,108
, and DA-mediated transmission is
involved in the acute aversive effects of opiate exposure
and withdrawal
109,110
, pointing to possible similarities in
the functional role of DA in both nicotine and opiate
addiction. Although future studies are required to
prolonged nicotine exposure, the learned associations
between its incentive motivational properties and the
environmental stimuli that become associated with these
effects might become dependent on DA signalling.
However, this idea does not explain why DA-mediated
transmission seems to carry a specific aversive signal in
the acute phase of nicotine exposure
8,10
, and a reinforcing
signal after chronic nicotine exposure.
A second explanation for the role of DA-mediated
signalling on the motivational effects of nicotine argues
for a consistent role for DA in the aversive aspects of
nicotine in both the acute and chronic phases of nicotine
exposure. The underlying idea is that a dysregulation of
DA-mediated signalling during nicotine dependence and
withdrawal after chronic exposure might be responsible
for the aversive effects of nicotine withdrawal. Whereas
activation of the nAChRs of DA neurons can signal an
aversive effect in the early phase of nicotine exposure
8,10
,
the eventual desensitization of these nAChRs, which
takes place after the desensitization of the nAChRs in
VTA GABA neurons
33
, might account for the tolerance
to the aversive properties of nicotine over time. Note,
however, that it is not known whether the nAChR desen-
sitization that is observed in vitro is analogous to the
NEUROLEPTIC
This term was originally coined
to refer to the effects of early
antipsychotic agents on
cognition and behaviour.
a
b
Acute nicotine
reward signal
Acute nicotine
aversion signal
TPP
VTA

Dopamine
Glutamate
inputs
Nucleus
accumbens
Desensitization of
acute nicotine
reward signal
Aversive nicotine
craving/withdrawal
Sensitized
incentive salience
TPP
VTA

Dopamine
Nucleus
accumbens
GABA
GABA
Glutamate
inputs
NMDA receptors
"7-containing
ACh receptors
"4#2-containing
ACh receptors
Figure 4 | An integrated model for nicotine reward signalling in the ventral tegmental area
(VTA). a | In the acute stage, the initial activation by nicotine of GABA (!-aminobutyric acid) neurons
in the VTA
32,33,40
produces rewarding effects through a GABA-dependent system that projects to the
tegmental pedunculopontine nucleus (TPP)
69,76,77
. These effects might involve the activation of
presynaptic nicotinic acetylcholine receptors (nAChRs) that contain the "7 subunit, as blockade of
this subunit interferes with the acute rewarding effects of nicotine
80,82
, but leaves the aversive signal
intact
82
. However, nicotine might also exert its motivational effects through direct actions on nAChRs
containing the #2 subunit and located on GABA or dopamine (DA) neurons, as pharmacological
blockade or genetic deletion of this subunit blocks both the aversive and rewarding effects of
nicotine
8,63,82
. In this model, nAChRs are distributed on both VTA neuronal populations, and nicotine-
induced activation of these receptors can therefore regulate the motivational effects of nicotine
through either non-DA or DA systems. b | With repeated nicotine exposure, however, the GABA
system that signals reward becomes desensitized, leading to a net shift in the action of nicotine to
the DA neurons
33,40
. This shift is mediated at least partly by increased glutamatergic input to the DA
system
33
. The shift in the functional balance between GABA and DA neuronal populations in the VTA
might lead to a dysregulated DA signal in the VTA, which in turn leads to the aversive psychological
effects of nicotine craving and withdrawal, and/or to the potentiation of the incentive salience of
nicotine and its compulsive use. NMDA, N-methyl-D-aspartate.
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R E V I E WS
to the addictive potential of nicotine? Studies on the
neurophysiological effects of nicotine within the VTA
provide new insights into how nicotine induces synaptic
plasticity within the mesolimbic DA system. These
studies might disclose a mechanism to account for the
shift from non-DA-mediated reward signalling in
the acute state to the involvement of DA-mediated
transmission in the development of compulsive nicotine
use. However, it will be important to examine how
these in vitro effects of nicotine might relate to what
happens in vivo during the development of addiction.
Finally, research that allows the dissection of the
contribution of specific subunits of the nAChR to the
motivational effects of nicotine and the development of
addiction might ultimately lead to a clear understanding
of which nAChR subunits are involved in the vulnera-
bility to the rewarding properties of nicotine, and how
alterations in specific nAChRs might lead to chronic
nicotine use and dependence.
examine more closely the functional role of DA-mediated
signalling in the early phases of nicotine exposure versus
the chronic state, the available studies in humans and
animals consistently indicate that chronic nicotine
exposure might lead to alterations in DA-mediated sig-
nalling, which might in turn lead to nicotine craving
and compulsive drug-seeking behaviours.
Conclusions and future directions
Despite the widespread effects of nicotine in the CNS,
converging evidence at the behavioural, molecular,
genetic and physiological levels points to the VTA and its
associated DA and non-DA systems as crucial mediators
of the motivational effects of nicotine. However, many
important questions remain to be answered. What func-
tional interactions take place between the systems that
subserve the aversive and rewarding effects of nicotine
during the development of nicotine dependence? Does
this functional interaction determine the vulnerability
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Acknowledgements
The authors thank CIHR for their support.
Competing interests statement
The authors declare that they have no competing financial interests.
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