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Nicotine addiction: Insights from recent animal studies

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Psychopharmacology (2002) 162:102–118
DOI 10.1007/s00213-002-1096-0
REVIEW
A. M. Mathieu-Kia · S. H. Kellogg · E. R. Butelman
M. J. Kreek
Nicotine addiction: insights from recent animal studies
Received: 13 August 2001 / Accepted: 7 March 2002 / Published online: 15 May 2002
© Springer-Verlag 2002
Abstract Rationale: Recent preclinical behavioral and
neurobiological research has characterized important
behavioral features and has identified neurobiological
substrates that may underlie nicotine reinforcement and
addiction. Objective: To examine recent advances on
nicotine exposure in preclinical models, from three per-
spectives: (a) the chronopharmacokinetics of nicotine,
(b) behavioral studies on nicotine reinforcement, with-
drawal, and reinstatement/relapse, and (c) effects of
nicotine on neurobiological substrates after repeated
exposure. Results: Preclinical studies can be used to
operationally model selected aspects of nicotine rein-
forcement, withdrawal, and reinstatement or relapse.
These may be used to investigate the functional in vivo
consequences of acute and long-term changes in neuro-
nal acetylcholine receptor populations that follow nico-
tine exposure. Behavioral studies focusing on distinct
stages of nicotine exposure (e.g., active reinforcement
vs. cessation or reinstatement) may also be used in parallel
with studies on dopaminergic function, a proposed sub-
strate for the reinforcing effects of nicotine, and of opioid
receptor function, a possible site of neuroadaptations
secondary to nicotine exposure. Conclusions: While no
single current animal model may capture the experience
of human smoking or nicotine addiction, increasingly,
separate animal models are capturing the full spectrum
of behavioral and neurobiological dimensions of this
complex condition.
Keywords Preclinical model · Drug-seeking behavior ·
Nicotinic · Dopamine · Opioid
A.M. Mathieu-Kia · S.H. Kellogg (✉) · E.R. Butelman
M.J. Kreek
Rockefeller University,
Laboratory on the Biology of Addictive Diseases, Box 171,
1230 York Avenue, New York, NY 10021-6399, USA
e-mail: kellogs@mail.rockefeller.edu
Tel.: +1-212-3278247, Fax: +1-212-3278574
Introduction
Over the past 20 years preclinical research studies have
been accumulating on the neurobiology of nicotine
addiction. This review emphasizes the recent literature
on the pharmacokinetics of nicotine, on animal models
to explore the distinct phases of nicotine addiction, and
on nicotinic neuropharmacology.
Chronopharmacokinetic characteristics of nicotine
Inasmuch as nicotine is thought to be the primary com-
pound in tobacco smoke that establishes and maintains
tobacco dependence, knowledge of its pharmacokinetic
characteristics is important for understanding the daily
smoking cycle. Smoking with frequent or deep inhala-
tion is the route of administration that allows for the
most rapid delivery of nicotine to the brain. Nicotine,
mainly through pulmonary absorption and via arterial
blood, reaches the brain within a few seconds. This
pattern is consistent with drugs that have a high abuse
potential (Quinn et al. 1997). As it is distributed to other
body tissues, circulating nicotine is rapidly oxidized into
cotinine, a major metabolite eliminated in urine. In
human smokers, as was also shown in recent data using
the stable isotopic nicotine technique (Benowitz et al.
1999), the initial distribution half-life (t1/2α) of nicotine in
the blood is estimated to be 4–10 min, and the elimination
half-life (t1/2β) is approximately 120 min (Benowitz
1988; Lunell et al. 2000; Perez-Stable et al. 1998). Arterial
nicotine concentrations peak approximately 20 s after
each puff, yielding increases in nicotine concentrations
in the order of 10 ng/ml (Rose et al. 1999). This rapid
arterial nicotine increase following each puff may be
especially relevant to the comparative reinforcing prop-
erties of cigarette smoking vs. other forms of nicotine
delivery, such as gum, transdermal patch, and nasal
spray (e.g., Gourlay and Benowitz 1997; Perkins et al.
1994; Schneider et al. 1996). After termination of each
cigarette, the blood level of nicotine rapidly peaks and

Fig. 1 Proposed circadian profile of circulating nicotine in regular
smokers. This theoretical schematic drawing models the intermittent
peaking-falling pattern during daylight hours and the circadian
fluctuations in nicotine concentration in the blood of human tobacco
smokers. Superimposed on these two different patterns of oscillation,
the overall level of nicotine gradually increases across the morning,
reaches a plateau during the afternoon to the late evening, and
finally decreases during the night to achieve low concentrations by
the next morning. Ideally, in animal models of nicotine addiction,
we should be able to reproduce a similar profile with respect to the
analogous circadian rhythm. White horizontal bars Daytime hours;
black horizontal bars nighttime hours. This drawing is arithmetically
constructed and is based on the short and long metabolic half-lives
of nicotine using a model of 8 cigarette smoking episodes a day.
This graph is inspired by, and very close to, the experimental data
obtained in human smokers (Benowitz et al. 1982)
falls. In addition to this intermittent spike pattern, the
overall level of nicotine across the daylight period grad-
ually increases in the morning, reaches maximal level
during the afternoon and late evening, and finally falls
during the night to achieve low but potentially active
concentrations by the next morning (Benowitz et al.
1982). This pattern repeats itself daily (Fig. 1). The
potential of nicotine to desensitize nAChRs should also
be considered in this context, since receptor desensitiza-
tion may occur in the presence of relatively low nicotine
concentrations (such as may be encountered during
“trough” periods; e.g., Marks et al. 1996; see also
“Primary molecular site of action: the neuronal nicotinic
acetylcholine receptors,” below).
In rodent models nicotine is also quickly absorbed
and its blood concentration rapidly declines in a biexpo-
nential fashion. In rats after ten puffs of cigarette smoke,
the t1/2α and t1/2β values of nicotine are 5 and 86 min,
respectively (Rotenberg et al. 1980). Similarly, after an
acute intra-arterial or intravenous administration of nico-
tine mean t1/2α and t1/2β of nicotine are approximately 10
and 90 min, respectively (Adir et al. 1976; Kyerematen
et al. 1988; Miller et al. 1977; Plowchalk et al. 1992;
Sastry et al. 1995). As for acute administration, calcula-
tions of the pharmacokinetic parameters in blood from
rats chronically treated with nicotine yield a global t1/2 of
44–49 min. This is a consistent value regardless of
whether rats receive the subcutaneous nicotine injections
two, four, or eight times a day over a 10-day period
(Rowell and Li 1997). In the brain the global t1/2 of nico-
103
tine is slightly longer than in the blood (Plowchalk et al.
1992; Rowell and Li 1997; Sastry et al. 1995). As the
number of injections increases, the brain levels of nico-
tine, which are on average two or three times higher than
those in the blood (Donny et al. 2000; Rowell and Li
1997), increase and reach a plateau which is difficult to
extrapolate from the blood values (Ghosheh et al. 2001).
Additional work is needed to establish the pharmaco-
kinetic profile of nicotine in specific brain regions and in
studies of behavioral models of addiction. Furthermore,
recent experiments have contributed to the development
of possible novel agonist pharmacotherapies for breaking
the cycle of nicotine addiction in humans. For example,
recent studies have determined that nornicotine (N-de-
methylated nicotine; an alkaloid present in tobacco, and
also a minor nicotine metabolite), was weakly self-
administered by rats but could antagonize intravenous
nicotine self-administration (SA; Bardo et al. 1999;
Green et al. 2000).
Acquisition and maintenance of nicotine-seeking
behavior
Numerous experiments have shown that nicotine serves
as a positive reinforcer, and this has been extensively
documented in diverse animal species (almost exclusively
male) including primates, dogs, and rodents (for reviews
see Goldberg et al. 1983; Henningfield and Goldberg
1983; Perkins et al. 1999; Stolerman 1999). Although the
conditioned place preference assay (Calcagnetti and
Schecter 1994; Clark and Fibiger 1987; Jorenby et al.
1990; Risinger and Oakes 1995) has been used in some
studies, the intravenous SA assay has been favored as a
more direct way of demonstrating that nicotine initiates
and sustains drug-seeking behavior (self-administration
by other routes has also been studied, e.g., Glick et al.
1996). However, to perfectly reproduce the route,
frequency, chronology, and intake pattern of smoking the
ideal approach would be to have an animal actually
smoke cigarettes or self-inhale smoke on a smoking
machine. In fact, rhesus monkeys and baboons do smoke
after this behavior has been established in an operant
situation. In some extreme cases they would smoke up to
40 cigarettes/day, for periods lasting up to 3 years (Ando
104
and Yanagita 1981; Rogers et al. 1985, 1988). Despite
the clear analogy to human behavior, studies using
smoking protocols with nonhuman primates have been
rare in the last decade, probably due to material and
technical demands.
As is commonly observed in intravenous SA assays, a
crucial experimental parameter that governs the acquisi-
tion of SA behavior is the unit dose of nicotine (all doses
in text are presented as nicotine base, unless otherwise
stated). The optimal acquisition dose is thought to be
around 0.01–0.03 mg/kg per intravenous injection in
many animal species (Corrigall and Coen 1989; Cox et
al. 1984; Donny et al. 1995, 1998; Goldberg et al. 1981;
Henningfield and Goldberg 1983; Risner and Goldberg
1983; Shoaib and Stolerman 1999; Shoaib et al. 1997;
Suto et al. 2001; Tessari et al. 1995). The maintenance of
nicotine-seeking behavior in animal models is also dose
dependent, and an inverted “U” function is usually
found. However, the overall function may be shallower
for nicotine than for other reinforcing drugs, and may
suggest comparatively less dose regulation for nicotine
vs. other reinforcing drugs (Lynch and Carroll 1999;
Rose and Corrigall 1997). The inverted “U” shape dose-
effect curve has also been observed in conditioned place
preference assays with mice (e.g., Risinger and Oakes
1995) and rats (Fudala and Iwamoto 1986).
Nicotine-seeking behavior has been examined in a
variety of procedural conditions, both analogous to and
different from the human smoking cycle. The issue of
restricted versus unlimited access to nicotine is central
because of concerns about how to best mimic human
smoking behavior with respect to both the frequency of
cigarette use and the sleep-wake cycle. Restricted access
to nicotine has been a common model, which may not
capture the experience of human smokers who have
access to tobacco at any time. In light of recent legislative
interventions in the United States, access to tobacco is
becoming more restricted, and increasing numbers of
smokers may actually be following a fixed or variable
interval pattern of SA (i.e., possibly similar to a “binge”
use pattern). As investigations go forward, it will be
increasingly useful to systematically compare restricted
access, unlimited access, and “binge” models.
In an example of research utilizing schedules of repet-
itive nicotine exposure, nicotine was administered ad
libitum to mice in their sole source of drinking water.
Mice, as nocturnal animals, drink primarily during their
active phase, and as a result their plasma levels of nico-
tine follow a circadian high-to-low profile similar to that
reported in human smokers (for reviews see Pietila and
Ahtee 2000). This oral intake approach leads to a rela-
tively slow nicotine absorption pattern that may not fully
capture common cigarette use patterns. Valentine et al.
(1997), in an attempt to more closely approximate
human nicotine use, developed a model in which rats
were allowed unlimited access to nicotine using an intra-
venous SA assay while respecting the circadian/meal
cycles. The four doses used (0.00375–0.03 mg/kg) were
low compared to the commonly used doses in restricted
access; nevertheless, the rats rapidly initiated SA behav-
ior. However, there was a relatively low rate of SA
behavior, and there was not a general distinction between
responding on the active and inactive levers. In these
conditions of unlimited drug access the maximal nicotine
intake was approximately 0.2–1.4 mg/kg per day, vs.
0.4–0.9 mg/kg per hour in the restricted access approach
(Corrigall and Coen 1989; Cox et al. 1984; Donny et al.
1995).
Other important factors (both similar to and different
from the human smoking cycle) that could influence the
nicotine-seeking behavior also include previous experi-
mental administration or SA of various compounds such
as cocaine (Epping-Jordan et al. 1999; Tessari et al.
1995), caffeine (Tanda and Goldberg 2000) or nicotine
itself. Thus, noncontingent exposure to nicotine can
facilitate the later acquisition of nicotine SA (Shoaib et
al. 1997), the development of conditioned place preference
(Shoaib et al. 1994), and the increased intake of nicotine
as shown in a two-bottle choice study (Maehler et al.
2000). Although the direct parallel between these findings
and human smoking behavior is unclear, these findings
may reflect the process by which a relatively small
number of cigarette exposures puts an individual at high
risk for developing nicotine addiction.
Within the SA literature, there has been a growing
interest in the difference between the fixed-ratio and the
progressive-ratio schedules. Markou et al. (1993) have
proposed that the fixed-ratio schedules are a measure of
the “hedonic” value of the drug while the progressive-
ratio schedules are analogous to the experience of moti-
vational incentive or “drug craving.” The “breaking
point” is seen as a potential measure of the “cost” of the
drug. Donny et al. (2000) used this model to evaluate
sex-based, motivational-incentive differences in rats
that could potentially parallel the greater difficulty that
women have with the cessation of smoking (Perkins et
al. 1999).
It has been recently proposed that stimuli associated
with smoking or with nicotine SA procedures (e.g., stim-
ulus lights) acquire conditioned reinforcer status, and
that this contributes to the maintenance of tobacco or
nicotine SA (Balfour et al. 2000; Di Chiara 2000; Donny
et al. 1999). This may be analogous to the sensory stimuli
(e.g., in the respiratory tract) that may be temporally
associated with rapid arterial nicotine increases during
cigarette smoking in humans (e.g., Rose et al. 1999).
Extinction of nicotine-seeking behavior
and withdrawal
Smoking cessation or periods of forced nicotine absti-
nence have been examined in animals undergoing
extinction of nicotine-seeking behavior or cessation after
chronic experimenter-delivered administration. In rodent
SA experiments studying extinction, when saline is sub-
stituted for nicotine, an overall decline in drug-seeking
behavior is usually observed. During the first substitu-

tion session some rats begin pressing the bar less fre-
quently while others demonstrated a typical “extinction
burst” – a rapid but short-lived increase in bar pressing
levels (Corrigall and Coen 1989; Donny et al. 1995;
Shoaib et al. 1999). Interestingly, the drug-seeking be-
havior remains above control levels for 4–13 sessions
before being completely extinguished (Chiamulera et al.
1996; Donny et al. 1995; Tessari et al. 1995); this resis-
tance to extinction further supports the view of nicotine
as a powerfully addictive compound (e.g., DiChiara
2000).
Early and long-lasting behavioral signs of extinction
were also produced by preadministration with a nicotinic
antagonist (Goldberg and Spealman 1982; Shoaib et al.
1997).
Nicotine withdrawal in animals consists of a syn-
drome of spontaneous or precipitated physical signs –
similar to those found during opiate withdrawal (including
teeth-chattering/chews, yawns, abdominal writhes/gasps,
ptosis, wet shakes/tremors, rearing, and jumping). In-
creases in body weight, decreases in spontaneous activity,
hyperphagia, and hyperdipsia are also used to evaluate
the withdrawal intensity (Hildebrand et al. 1997; Levin
et al. 1987; Malin et al. 1992). In rats the discontinuation
of subcutaneous nicotine infusions (3.2–3.6 mg/kg per
day) produces a constellation of spontaneous behavioral
signs during the 2 days following cessation (Hildebrand
et al. 1997; Malin et al. 1992, 1994; Watkins et al.
2000a). Nicotinic antagonists are also able to precipitate
all of these abstinence symptoms, and a subsequent nico-
tine injection (e.g., 0.15–0.4 mg/kg subcutaneously)
attenuates their intensity (Hildebrand et al. 1997; Malin
et al. 1994, 1998). In a study using daily intermittent
nicotine injections in mice, mild somatic withdrawal
signs were reported between 24 and 48 h after the final
bolus, and some of them persisted for 3–4 days (Isola et
al. 1999). When these studies are contrasted, continuous
and intermittent exposures share similar withdrawal
symptom while following different temporal courses. It
is to be noted that none of the studies to date on with-
drawal signs have used a SA model (to our knowledge),
and this approach would more closely mimic the behavior
of smokers.
The intracranial self-stimulation (ICSS) model has
also been able to measure the reinforcing properties of
nicotine exposure and the state change (or “presumed
dysphoria”) that follows its termination. In the ICSS
model the effect of nicotine is thought to mimic the power
and rewarding effect of each electrical stimulation (for a
review see Wise 1996). As a result the ICSS threshold is
lower for the nicotine-treated animals than for those
receiving vehicle. This stimulus substitution is reached
as early as the second day of administration and lasts as
long as nicotine is repeatedly injected and not blocked
with nicotinic antagonists (Bauco and Wise 1994;
Bespalov et al. 1999; Bozarth et al. 1998a, 1998b;
Huston-Lyons et al. 1993; Ivanová and Greenshaw
1997). In a contrasting effect, animals maintained on a
continuous infusion of nicotine by osmotic pump do not
105
show this same change in the ICSS (Epping-Jordan et al.
1998). Nonetheless, once the continuous nicotine infu-
sion is terminated, the spontaneous withdrawal condition
elevates ICSS thresholds. The rat may be postulated to
be in a “dysphoric” state, a condition that may parallel
the “negative mood state” seen in smokers, which is
typified by irritability, lack of concentration, anxiety, and
craving (Benowitz 1988; see also below). Similarly, con-
ditioned place aversion induced by precipitated nicotine
withdrawal may provide a sensitive measure of internal
states (e.g., discriminative or hedonic) produced by nico-
tine withdrawal in animals (Ise et al. 2000; Watkins et al.
2000a).
Other studies have also attempted to examine the
“subjective” or interoceptive state of animals when they
experience nicotine withdrawal. Spontaneous withdrawal
in rats has been marked by an increased “sensorimotor
reactivity” response to acoustic startle (Acri et al. 1991;
Harris et al. 1986; Helton et al. 1993, 1997; Rasmussen
et al. 1997).
The withdrawal state after chronic, repeated nicotine
administration is also notable for its significant disrup-
tion of operant behaviors not directly linked to the drug-
seeking behavior. When nicotine access is terminated,
the reinforcement potential of food or sweetened solu-
tion is suppressed, and this interference is immediately
reversed when nicotine is again available (Carroll et al.
1989; Corrigall and Coen 1989). Similarly, the abrupt
cessation of nicotine administration in rats trained on a
shock-avoidance schedule is also associated with a re-
duction in lever-pressing responses and with an increase
in the number of shocks received (for a review see
Balfour 1991). These behavioral alterations are seen as
acute signs of withdrawal and could be compared to
the loss of the “psychological benefits” of smoking
commonly described by smokers during abstinence.
Reinstatement model of nicotine-seeking behavior
and relapse
Experimental relapse from nicotine addiction has been
examined through the reinstatement of previously extin-
guished nicotine-seeking behaviors, using spontaneous
recovery conditions, nicotine priming doses, or stress-
inducing stimuli. Animals removed from their operant
chamber or in saline substitution protocols spontaneously
recover drug-seeking behavior at levels comparable to
those observed during the preextinction period within
one session (Donny et al. 1995; Goldberg et al. 1981;
Valentine et al. 1997). Similarly, after 6–20 sessions of
saline substitution, the availability of nicotine progres-
sively reinitiates SA to preextinction levels (Goldberg et
al. 1981; Tessari et al. 1995). Lastly, after a 3-week period
of nicotine withdrawal, rats reexposed to the drug-taking
environment spontaneously recover their previous behavior
(Shaham et al. 1997). Whatever the experimental condi-
tion, spontaneous recovery of SA occurs after either a
short or long cessation period, and this phenomenon
106
illuminates the connection between environmental factors
and relapse.
Another approach to study relapse is to use an acute
priming nicotine injection to reinstate nicotine SA. An
acute priming nicotine dose (either intravenous or subcu-
taneous) reinstates nicotine SA after 4–13 days of saline
substitution (Chiamulera et al. 1996; Shaham et al.
1997). Interestingly, higher levels of reinstatement of
nicotine SA are observed with a lower priming dose of
nicotine (Chiamulera et al. 1996). Thus, in addition to
potentially conditioned environmental stimuli, nicotine-
seeking behavior can also be reinitiated through noncon-
tingent nicotine reexposure.
Intermittent footshock as a stressor is also an effective
method of reinstating nicotine-seeking behavior – even
after periods ranging from 5 days to 2 weeks (e.g., Buczek
et al. 1999). This supports the clinical observation that
stress can be a major precipitant of relapse; continued
work in this area is crucial as this is a major therapeutic
intervention point for smoking-cessation medications.
Animal models of the “psychological” experience
of smoking
A number of recent studies have attempted to model the
wide variety of experiences and use patterns that smokers
report. Areas of investigation have included psychological
mood states, such as depression and anxiety, and the
cooccurring use of other substances, such as caffeine and
alcohol.
The relationship between nicotine and depression has
been one of growing interest. Studies have shown that
cigarette smoking is quite common among depressed
individuals and that individuals with a long history of
depression are less likely to succeed at smoking cessation
(Tizabi et al. 1999). In fact, buproprion, an antidepres-
sant, is prescribed to patients seeking to discontinue
smoking (NIDA 1998).
Semba et al. (1998) used a “learned helplessness”
model that involved shock and an escape test in male rats
and found that chronic administration of nicotine may
have an apparent antidepressant effect, and that meca-
mylamine, a nicotinic antagonist, reversed this effect of
nicotine. Similarly, Tizabi et al. (1999) examined the
apparent antidepressant effects of nicotine in the “forced
swim” model of depression with two related rat lines.
The Flinders Sensitive Line (FSL) has been specifically
bred to be a “depression-prone” rat, and the Flinders
Resistant Line (FRL) has been bred to be a “depression-
resistant” rat. After both acute and chronic (14-day)
administration of nicotine, immobility was decreased in
the “depressed” FSL rat but not in the FRL rats. Djurič et
al. (1999), also using the forced swim-test with female
FSL and FRL rats (found after 14 days of oral nicotine
ingestion), an antidepressant effect of nicotine that did
not interact with genetic background.
Another area of investigation is the relationship be-
tween smoking and anxiety, focusing on the anxiolytic/
anxiogenic effects of nicotine and nicotine withdrawal.
Ouagazzal et al. (1999) found that nicotine had no effect
at the lower doses, but was anxiogenic in the elevated
plus-maze test at higher doses. Irvine et al. (2001a) in a
study with male Wistar rats examined the effects of nico-
tine in the social interaction test after 4 weeks of nicotine
SA and then, again, 24 to 72 h after its cessation. Rats
that self-administered nicotine showed less interaction
with other rats in the social interaction test than the
control group (an apparent nicotine-induced, anxiety-like
effect). These group differences disappeared during the
nicotine cessation period. Irvine et al. (2001a) concluded
that “nicotine self administration is not maintained
because of its anxiolytic effect, but despite or because
of, its anxiogenic effect.” They also pointed out that
the findings of the animal studies were in conflict
with common assumptions about the behavior of human
smokers.
The cessation of nicotine administration also appears
to induce anxiety in animals, and this has been proposed
as paralleling the withdrawal symptoms that serve as
negative reinforcers working to maintain the use of
tobacco. Classical rodent models of “anxiety,” such as
the black/white box test (Costall et al. 1989), the elevated
plus-maze test (Irvine et al. 2001b), and the social inter-
action test (Irvine et al. 1999), have been used to evaluate
the nicotine withdrawal state. An anxiogenic response
first appeared within 8–96 h following the cessation of
chronic experimenter-delivered nicotine in these settings.
However, anxiogenic effects were not detected 1 or
3 days following the end of a 4-week period of intrave-
nous nicotine (0.03 mg/kg per injection) SA (Irvine et al.
2001a; see above). To summarize, the overall relation-
ship between nicotine and anxiety remains complex and
unclear.
Tobacco use and cigarette smoking often occur con-
currently with the use of other substances. Recent studies
have attempted to examine two common combinations –
nicotine and caffeine and nicotine and alcohol. Shoaib et
al. (1999) reported that caffeine markedly increased the
reinforcing properties of nicotine using an SA model,
and its consequent removal diminished the reinforcing
properties of nicotine. This finding supports a role for
caffeine as a possible contributor to nicotine SA and
relapse (Shoaib et al. 1999).
Other studies examined the interaction between nico-
tine and alcohol. Here the emphasis has been on the
effect of nicotine on alcohol consumption. Nadel and
Samson (1999), using male Long-Evans rats, found that
nicotine had only a slight effect on increasing alcohol
SA. Lê et al. (2000), using male Wistar rats, found a
complex relationship between exposure to nicotine and
alcohol consumption. Nicotine only impacted alcohol
SA at higher doses (0.8 mg/kg), and the effect was
biphasic, as it actually suppressed alcohol consumption
at first and then increased it. The authors suggested that
this biphasic effect of nicotine on alcohol consumption
might explain conflicting reports about the relationship
between these substances in the literature.

Gender and genetics as mediating variables
in the effects of nicotine
In a comprehensive review, Perkins et al. (1999) dis-
cussed the emerging evidence that men and women differ
in their responses to smoking in general. The human data
point to a pattern in which the relative importance of
“nonnicotine” factors that are involved in smoking
behavior is greater for women than for men. This may
include such factors as pleasure from the smoke itself,
social reinforcements for smoking, comfort from having
something to manipulate in social situations, and gratifi-
cation from oral stimulation. Faraday et al. (1999) have
also pointed out that women are more inclined to see
smoking as a useful mechanism for coping with social
situations or unpleasant affective states. Perkins et al.
(1999) went on to point out that these differences have
had troubling consequences for women smokers who are
seeking to quit; mainly that women have been less suc-
cessful than men in studies using nicotine-replacement
interventions. Interestingly, women respond better than
men in studies in which such nonnicotine medications as
clonidine or buproprion are used (Perkins et al. 1999).
The animal literature has supported this pattern to
some degree as well. Perkins et al. (1999) note that nico-
tine appears to be equally reinforcing for males and fe-
males, but that aspects of the experimental environment
that may become associated with nicotine may contribute
a more significant role in the maintenance of nicotine SA
for females than for males.
Faraday et al. (1999) examined the interaction of gender
and housing (single versus group) on nicotine-induced
locomotion in Long-Evans rats in a Plexiglass arena. The
emerging patterns showed that there was an interaction
between gender and housing, and nicotine affected the
arousal and exploration behavior of males, while it
appeared to have had an “anxiolytic-like” effect on the
female rats.
Donny et al. (2000), examined sex differences in SA
using Sprague-Dawley rats. In this study they used both
fixed-ratio schedules, which they postulated reflect the
hedonic aspect of nicotine, and progressive-ratio sched-
ules, which they suggest better reflect “drug craving” or
incentive motivation (Markou et al. 1993). Their finding
was that while that there was no significant sex differ-
ence in the fixed-ratio schedule, females had higher
breaking points in the progressive-ratio schedule. The
females, in both contingency paradigms, also demon-
strated a shorter latency to first infusion, and this may be
interpreted as another index reflecting nicotine incentive
motivation.
Lastly, in an attempt to look at the interplay between
genetics and the SA of drugs of abuse, Todte et al. (2001)
examined the propensity of Brown-Norway rats (BNR)
and Wistar-Kyoto rats (WKR) to orally self-administer
ethanol, nicotine, cocaine, and morphine. The WKR
strain is known for its higher emotionality and its lower
plasma stress catecholamine responses (Todte et al.
2001). They also examined age as an important mediating
107
Fig. 2 Anatomical sites of action for nicotine in the rat brain. This
sagittal section illustrates the distribution of high-affinity binding
sites for [3H]nicotine. SC Superior colliculus, AV anteroventral
nucleus, VL ventrolateral nucleus, Rt reticular nucleus, Cpu dorsal
striatum, Acb nucleus accumbens, SNC/VTA substantia nigra com-
pacta/ventral tegmental area. (Slightly modified from Clarke et al.
1985, copyright by the Society for Neuroscience)
variable. Both strain and age differences were found, with
the WKR consuming more ethanol and nicotine than the
BNR, and the older BNR consumed less nicotine and
ethanol than the younger (Todte et al. 2001). These and
other (Robinson et al. 1996; Stolerman et al. 1999) recent
studies therefore support future investigation of the influ-
ence of genetic factors in nicotine SA.
Primary molecular site of action:
the neuronal nicotinic acetylcholine receptors
Nicotine specifically binds to the nicotinic receptors
(nAChRs), which mediate initially its effects, and are
widely distributed in the brain of many species including
humans (for a review see Paterson and Nordberg 2000).
A precise map of the distribution of nAChR (Fig. 2) was
first established using quantitative autoradiography with
[3H]nicotine (Clarke et al. 1984, 1985), and later with
other approaches such as immunohistochemistry (Deutch
et al. 1987; Swanson et al. 1987) and in situ hybridiza-
tion (Dineley-Miller and Patrick 1992; Flores et al. 1992;
Wada et al. 1989). Due to the wide distribution of nAChRs
nicotine addiction or chronic administration may alter
the function of most, if not all, of the brain regions and
various neurotransmitter systems.
Although nAChRs are located in many peripheral tis-
sues, the rewarding properties of nicotine are mediated
by the interaction of this alkaloid with nAChRs in the
CNS. In animals, systemic administration of a nicotinic
antagonist which crosses the blood-brain barrier (meca-
mylamine) attenuates the intravenous SA of nicotine
(Corrigall and Coen 1989; Goldberg et al. 1981; Risner
and Goldberg 1983). Similarly, mecamylamine pretreat-
ment blocks the effects of nicotine in a conditioned place
preference assay (Fudala et al. 1985) and inhibits the
stimulant effect of nicotine on locomotor activity, in
chronically treated rats (Benwell et al. 1995). During
108
precipitated nicotine withdrawal, recent data demonstrate
that central nAChRs mediate elevated brain stimulation
reward thresholds, whereas both central and peripheral
nAChRs appear to mediate the somatic withdrawal syn-
drome (Watkins et al. 2000a, 2000b).
Neuronal nAChRs are pentameric and allosteric
membrane protein complexes. They are members of the
superfamily of ligand-gated ion channels permeable to
cations (Na+/K+, Ca2+; see Changeux et al. 1984), and
this ionic flux leads to a depolarization and an excitatory
response of neurons. Each neuronal nAChR subunit is
encoded by a separate gene. To date, of the 12 distinct
genes cloned, the expression of nine has been found in
the brain of rat or primate. These subunits have been
named α2, α3, α4, α5, α6, α7, β2, β3, and β4. There-
fore, multiple combinations of some but not all of these
five subunits can form functional heteromeric (α with β)
or homomeric (α) nAChRs with distinct pharmacophysi-
ological features (Lukas et al. 1999; Zoli et al. 1998). In
addition to this molecular complexity, the regional distri-
bution of the different subunits differs among brain areas
and among neuronal populations. In brain, the most
widely and concurrently expressed subunits are α4 and
β2. In contrast, the patterns of α7, α3, and α5 subunit
expression are more limited in both their density and
localization. The α2, α6, β3, and β4 subunits are limited
to only a few brain regions. Although the molecular
diversity of the initial site of action for nicotine is well
explored, it is still unknown whether one (or several)
particular subunit combination of nAChR preferentially
mediates the reinforcing effects of nicotine, or whether a
particular genotype(s) is involved in tobacco consump-
tion behavior. Studies with subtype-selective nAChR
antagonists, focusing on their ability to modulate nicotine’s
reinforcing (and other) effects would therefore be of
value. For example, a recent study has shown that the
α4/β2 nAChR selective antagonist erysodine blocked the
discriminative and reinforcing effects of nicotine in rats
(Mansbach et al. 2000).
Studies using transgenic mice that lack specific sub-
units of the nAChR could also help determine which
subunits play a fundamental role in nicotine addiction
(for reviews see Cordero-Erausquin et al. 2000; Marubio
and Changeux 2000; Picciotto et al. 2000). Several (but
not all possible) mice lacking one or two subunits have
been generated. While some of these appear to have
multiorgan dysfunctions and impaired survival, others
reach adulthood (Bansal et al. 2000; Caldarone et al.
2000; Franceschini et al. 2000; Marubio et al. 1999; Paylor
et al. 1998; Ross et al. 2000; Rossi et al. 2001; Vetter et
al. 1999; Xu et al. 1999a, 1999b). Their behavior has not
been fully explored in the context of nicotine reinforce-
ment. While α7 subunit-deficient mice have no detect-
able abnormalities in the density of [3H]nicotine sites
(Orr-Urtreger et al. 1997), α4 and β2-subunit deficient
mice have lost almost all their sites in all brain regions
(Marubio et al. 1999; Ross et al. 2000). Interestingly, β2
subunit-deficient mice which have been trained to self-
administer cocaine cease their nose-poking behavior
when nicotine is substituted for cocaine (Epping-Jordan
et al. 1999; Picciotto et al. 1998). Similar studies with
α4- or α7-deficient and viable mice have not been de-
scribed to date. Nicotine-induced place preference exper-
iments using these three types of genetically altered mice
have also not been documented, although a recent report
suggests that the β2 subunit contributes to the motiva-
tional effect of cocaine (Zachariou et al. 2001). Taken
together, it is therefore possible that the reinforcing and
motivational properties of nicotine are mediated by a
neuronal nAChR made of at least one β2 subunit.
In contrast to many other receptors that are down-
regulated following a chronic exposure to their agonist,
nAChR are unexpectedly up-regulated after chronic
nicotine administration (Marks et al. 1983; Schwartz and
Kellar 1983; for a review see Wonnacott 1990). Instead
of a decrease in the number of nicotine binding sites, an
increase following chronic nicotine administration has
been observed in postmortem brain studies of rodents
(Marks et al. 1992; Pauly et al. 1991, 1996; Zhang et al.
1994) and humans (Benwell et al. 1988; Breese et al.
1997; Court et al. 1998) as well as in the living brain of
baboons (Kassiou et al. 2001). Chronic exposure of rats
to mainstream cigarette smoke for more than 3 months
resulted in an increase in nicotine binding sites in the
cerebral and cerebellar cortices and more modestly in the
striatum but not in the thalamus or hippocampus where
nAChR are also densely expressed (Yates et al. 1995).
With few exceptions studies using multiple injections of
various doses of nicotine have shown increases in nico-
tine binding sites in the cortex, the striatum, and the
hippocampus (Collins et al. 1988; Coutcher et al. 1992;
el-Bizri and Clarke 1994; Flores et al. 1997; Ksir et al.
1987; Lapchak et al. 1989; Nordberg et al. 1989; Romanelli
et al. 1988; Rowell and Li 1997; Ulrich et al. 1997; Wall
et al. 2000; Zhang et al. 1994). The up-regulation of
nicotine binding sites, which was also found in the
brains of rats that self-administered nicotine (Donny et
al. 2000), occurs largely in specific cerebral regions.
This may reflect a differential responsiveness of nAChR
to chronic exposure to nicotine, possibly related to a dif-
ferential subunit composition. Immunoprecipitation pro-
tocols or binding studies using specific subtype ligands
suggest that the subunit composition of the up-regulated
nAChRs is made up of α4 and β2 subunits in the cortex
and the hippocampus of rats chronically treated with
nicotine and not of α3 or β4 subunits (Flores et al. 1992,
1997). Chronic nicotine exposure in mice also led to an
increase in α-bungarotoxin sites (thought to represent
nAChR that contain the α7 subunit; Marks et al. 1983;
Pauly et al. 1991), although this has not been found in
the postmortem brains of human smokers (Court et al.
1998).
It has been proposed that simultaneously with an
increased number of nicotine sites a functional desensiti-
zation of the nAChR occurs during chronic exposure to
nicotine. Indeed, the nAChR is an allosteric protein com-
plex with at least three conformational states. The inter-
action of nicotine or acetylcholine (low affinity) with the

nAChR induces a quick transition from the resting state
(channel closed) to the active state (channel opened with
high affinity). If nicotine exposure is prolonged, the
receptor slowly enters into a desensitized state (channel
closed) that is unresponsive to the agonist. The in-
creased number of nicotine sites could be a neuronal
response to the accumulation of receptors desensitized
after long-term nicotine exposure. Desensitization of
nAChR populations may be relevant in human smokers,
since prolonged exposure to low nicotine concentrations
(such as may be observed in “trough” periods or at
nighttime) may result in receptor desensitization (see
“Chronopharmacokinetic characteristics of nicotine”
above; see also Marks et al. 1996; Rosecrans and Karan
1993)
In mice regardless of the nicotine administration pro-
tocol used changes in nAChR numbers are not attribut-
able to transient or sustained changes in nAChR subunit
mRNA levels (Pauly et al. 1996). The nature of the
mechanisms involved in the up-regulation of nicotine
receptors is therefore likely posttranscriptional, although
increased synthesis may not be totally excluded (Ryan
and Loiacono 2001; Yu et al. 1996).
Since the reported up-regulation of nAChR is also
accompanied by enhanced behavioral responses such as
locomotor activity or cognitive performance, this molec-
ular event might be related to the behavioral sensitiza-
tion observed during chronic nicotine exposure (Abdulla
et al. 1996; Ksir et al. 1985, 1987; Nisell et al. 1996). Of
greater salience to the field of nicotine addiction is the
question of whether changes in the density of nicotinic
sites are a crucial molecular event in the early abstinence
phase. It could be hypothesized that as soon as the con-
centration of nicotine is no longer sufficient to desensi-
tize nAChR, the desensitized nAChR return to their rest-
ing state. Consequently, when nicotine exposure is termi-
nated, the total number of functional nAChR potentially
sensitive to nicotine (or acetylcholine) should be greatly
increased at the cell surface, thus rapidly altering the
physiology of neuronal circuits. However, in adult
rodents the return of the up-regulated receptors to basal
values takes at least 1 week after the cessation of nico-
tine administration (although not in all brain regions;
Collins et al. 1990; Koylu et al. 1997; Pietila et al. 1998).
In addition, a more robust and longer lasting receptor
up-regulation was observed in rats exposed to nicotine
during the adolescent period (Trauth et al. 1999). Overall,
it is possible that the persistent up-regulation of nicotine
binding sites during cessation may play a role in the
intensity of the early withdrawal symptoms and therefore
the likelihood of relapse.
Knowledge of the neurobiological and behavioral
consequences of the increase in nicotine binding sites in
various brain regions is therefore important to extend our
understanding of altered function in active smokers as
well as in others exposed to nicotine (such as nonsmokers,
newborns exposed during pregnancy, and ex-smokers
therapeutically exposed to nicotine through nasal spray,
transdermal patches, or gum).
109
Downstream sites of action: the mesolimbic
dopamine neurons
Although the function of numerous neurotransmitter
systems expressing nAChR could be altered by nicotine,
the initial reinforcing properties of this compound are
thought to be mediated primarily through the mesolimbic
and mesocortical dopamine (DA) systems. These neuro-
nal pathways consist primarily of the DA neurons from
the ventral tegmental area (VTA) that project to various
cerebral regions, notably the nucleus accumbens and
various limbic cortices. These brain areas are involved in
reward functions and mediate the actions of natural
reinforcers as well as many drugs of abuse.
To our knowledge, SA of nicotine directly into those
DA terminal areas has not been described to date. How-
ever, direct administration of nicotine in the mesolimbic
and mesocortical regions substitutes for the discrimina-
tive stimulus of nicotine established through subcutane-
ous injection (Miyata et al. 1999). The importance of
those regions, especially the nucleus accumbens, was
also supported by the finding that bilateral lesions of
DA neurons led to a reduction in intravenous nicotine
SA (Corrigall et al. 1992; Singer et al. 1982). A bilateral
intra-accumbens microinjection of 6-hydroxydopamine
into the accumbens also abolished the locomotor stimu-
lant effect of subcutaneous nicotine in rats (Clarke et al.
1988). Similarly, the blockade of DA transmission by
selective DA antagonists in nonlesioned rats also
reduced nicotine SA (Corrigall and Coen 1991b) and
completely blocked nicotine-conditioned place prefer-
ence (Acquas et al. 1989) and nicotine-induced ICSS
(Huston-Lyons et al. 1993). These observations, in sum,
suggest a major role for the DA neurons, especially
from the mesolimbic system, in mediating the reinforcing
effects of nicotine.
Nicotinic AChRs are localized on the cell bodies of
DA neurons in the ventral mesencephalon as well as on
DA terminals in the nigrostriatal and mesolimbic path-
ways (Clarke and Pert 1985; Clarke et al. 1984; London
et al. 1985). Most of those DA neurons express abun-
dantly the α6 and β3 nAChR subunit mRNA (Le Novere
et al. 1996) and also at moderate levels α3, α4, α5, and
β2 subunit mRNA (Dineley-Miller and Patrick 1992;
Duvoisin et al. 1989; Sorenson et al. 1998; Wada et al.
1989). Although there is no unique expression pattern of
these various nAChR subunits within DA neurons from
the VTA, the activation of nAChR from this area alone
could explain some of the behavioral effects seen after
repeated systemic administration of nicotine. Indeed,
infusion of a nicotinic antagonist into the VTA prior to
intravenous nicotine SA sessions significantly decreases
the number of nicotine infusions obtained (Corrigall et
al. 1994). Moreover, repeated applications of a nicotinic
agonist (cytisine) directly into the VTA induced a place
preference for the cytisine paired compartment (Museo
and Wise 1994), and repeated applications of nicotine
showed a progressive increase in the locomotor response
in rats (Panagis et al. 1996; Reavill and Stolerman 1990).
110
These data support the hypothesis that the α3, α4, α5,
α6, β2, and β3 subunit containing nAChR, which are
localized on the mesolimbic system, contribute to both
the reinforcing properties and the psychostimulant
effects of nicotine.
The interaction of nicotine with nAChR localized on
the VTA-accumbens pathway causes profound modifica-
tions in the functioning of DA neurons. Acute as well as
chronic intermittent administration of nicotine leads to
an increase in the activity of midbrain DA neurons by
accelerating the firing of neurons and by switching their
activity from regular to burst firing patterns (Grenhoff et
al. 1986; Lichtensteiger et al. 1982; Mereu et al. 1987;
Nisell et al. 1996). Moreover, cessation of continuous
nicotine administration by subcutaneous osmotic mini-
pump (6 mg/kg for 12 days) also alters firing rates of
midbrain DA neurons (Rasmussen and Czachura 1995).
These changes in electrophysiological activity, especially
burst firing, could be associated with greater neurotrans-
mitter release in the terminal fields of DA neurons, initi-
ating neurochemical changes within those neurons or
within neurons from projection areas.
An acute systemic injection of nicotine, such as with
other drugs of abuse, increases the extracellular concen-
trations of DA in the terminal fields of the mesolimbic
system (Imperato et al. 1986; Maisonneuve and Glick
1999; Mifsud et al. 1989; Pontieri et al. 1996; for a
review see Di Chiara 2000), the nigrostriatal pathway
(Di Chiara and Imperato 1988; Toth et al. 1992), and the
mesocortical pathway (Bassareo et al. 1996; Summers
and Giacobini 1995; Toth et al. 1992). Repeated nicotine
injections in rats (0.4 mg/kg nicotine tartrate subcutane-
ously for 7 days) increased the dopamine release caused
by local nicotine administration in the striatum, as mea-
sured with in vivo microdialysis (Marshall et al. 1997).
Interestingly, this effect was not observed if the same
daily nicotine dose was administered as a continuous in-
fusion (Marshall et al. 1997). In other experiments with
chronically treated rats, a systemic injection of nicotine
increased DA release in both the prefrontal cortex (Nisell
et al. 1996) and the nucleus accumbens (Benwell et al.
1994; Nisell et al. 1997; Reid et al. 1996). The nicotine-
induced DA release is of the same amplitude or higher in
chronically (as compared to acutely) injected rats. Rats
treated daily with nicotine may have both higher basal
extracellular DA concentrations in the nucleus accumb-
ens, as well as an increased DA release in response to a
further nicotine challenge (Benwell and Balfour 1992;
Benwell et al. 1994, 1995; Damsma et al. 1989). Local
intrategmental mecamylamine injection reduced DA
overflow in the ipsilateral nucleus accumbens of rats
treated chronically with nicotine (by osmotic minipump)
for 14 days (Hildebrand et al. 1999). A similar effect was
observed after the termination of nicotine administration
(Fung et al. 1996). These observations suggest that
dynamic DA transmission is preserved (and may be
enhanced) in the mesolimbic and corticolimbic systems
during intermittent nicotine administration, and may be
decreased during withdrawal.
Nicotinic receptors localized on DA cell bodies or
terminals could initiate nicotine-induced DA release. In
fact, in vivo microdialysis studies have shown that the
local infusion of nicotine directly into the VTA is suffi-
cient to increase the DA extracellular concentration in
the nucleus accumbens (Marshall et al. 1997; Mifsud et
al. 1989; Nisell et al. 1994). However, although persis-
tent effects are observed when nicotine is administered
locally to the DA cell bodies, local administration to the
terminal fields of DA neurons can also stimulate (albeit
transiently) DA release (Mifsud et al. 1989; Nisell et al.
1994). VTA or somatodendritic nAChRs have been
implicated in the effects of nicotine in SA, conditioned
place preference assays, or on spontaneous activity. Thus
nAChRs of the VTA have a crucial role in both nicotine-
induced DA release and in the reinforcing properties of
nicotine.
A possibly contrasting line of evidence involves the
finding that schizophrenic patients receiving haloperidol
(a dopaminergic D2-like antagonist) smoke at high rates
(e.g., McEvoy 1995). It is possible that this behavior
continues because high levels of tobacco use may allow
the individual to compensate for decreases in dopamine-
based reinforcement caused by haloperidol (see also
Rose and Corrigal 1997) and because the individual may
be receiving continued reinforcement from nonnicotine
stimuli involved in smoking.
Several investigators have also suggested that the
maintenance of drug SA (and particularly nicotine or
tobacco) may also depend critically on cues associated
with smoking, which may acquire “conditioned reinforcer”
status by their pairing with self-administered nicotine
and its secondary dopamine release (Balfour et al. 2000;
Di Chiara 2000; Donny et al. 1999; see also above). Of
particular relevance to this hypothesis is the temporally
contingent relationship between smoking behavior (e.g.,
puff inhalation) and its associated sensory stimuli or
“cues”, with a rapid rise in intra-arterial nicotine levels
(see “Chronopharmacokinetic characteristics of nicotine”,
above). It has also been suggested that the maintenance
of nicotine or tobacco SA is especially dependent on
possible secondary reinforcers, due to the presumed
desensitization of nAChRs after prolonged exposure
(Balfour et al. 2000).
The endogenous opioid system and its connection
to the withdrawal process
Preclinical studies on nicotine reinforcement exploring
the involvement of the endogenous opioid system –
µ-, δ-, or κ-opioid receptors or their endogenous agonist
peptides, the enkephalins, dynorphins, and β-endorphin
– appear to be rare. In addition, in most animal studies
no conclusive involvement has been found (for a review
see Pomerleau 1998). For example, a preinjection with
κ/µ-opioid receptor antagonist naltrexone prior to SA
sessions did not affect the reinforcing properties of nicotine
(Corrigall and Coen 1991b), and an injection of naloxone
Table 1 Early to late effects subsequent to a chronic (intermittent or continuous) nicotine administration on the endogenous opioid system in the male rodent brain

POMC mRNA End peptide ppEnk mRNA Met-Enk peptide ppDyn mRNA [3H]-DAMGO
site Bmax and Kd

POMC system
Chronic nicotine effect (<2 h)
Early withdrawal (4 h–≤3 d)
Late withdrawal (7 d–21 d)
Enkephalin system
Chronic nicotine effect (≤2 h)
Early withdrawal (24 h–≤3 d)
Late withdrawal (7 d–14 d)
Dynorphin system
Chronic nicotine effect (≤2 h)
Early withdrawal (24 h)
Mu receptor
Chronic nicotine effect (≤2 h)
a Dhatt et al. (1995)
b Hollt and Horn (1992)
c Houdi et al. (1998)
=Hypothalamus,
anterior pituitaryb;
↑anterior pituitaryb;
↓intermediate pituitaryb
↓Hypothalamusf ↓Hypothalamusg;
=pituitaryg
=Hypothalamusf; ↑Hypothalamusg
↓hypothalamusg;
↓hypothalamusg
=Striatum, accumbens, =Hippocampus, cortexa;
hippocampus, hypothalamus, ↑Hypothalamusa;
cerebellumb,c,e; ↓striatum, midbrainh
↓striatum, hippocampusc
=Striatum, accumbens, =Striatum, hippocampus,
cerebellumc,d; ↑striatum, hypothalamus, pituitaryg;
accumbens, hippocampusc,d,f; ↑striatuma
↓striatumc
=Striatum, hippocampus, =Striatum, hippocampus,
cerebellumc hypothalamus, pituitaryf
=Striatum, accumbens,
hippocampus,
hypothalamusb,e;
↓ventral accumbense
=Striatum, accumbensd
=Striatum,
midbraing
d Mathieu et al. (1996) g Rosecrans et al. (1985)
e Mathieu-Kia and Besson (1998) h Wewers et al. (1999)
f Rasmussen (1998)
111
112
did not dose-dependently block the low reward threshold
induced by nicotine in the ICSS assay (Huston-Lyons
and Kornetsky 1992). Tests of generalization to mor-
phine in drug-discrimination assays were also negative
(Stolerman 1989). Other data show that the selective
δ-opioid receptor antagonist naltrindole, given in combi-
nation with nicotine for 3 days, failed to prevent the
expression and the development of sensitization to the
locomotor-activating effects of nicotine (Heidbreder et
al. 1996). While opioid antagonists have been shown to
have no direct impact on the effects of nicotine, studies
with opioid agonists suggest a possible subtype-selective
role. For example, the κ-opioid agonist U69593 did not
prevent the sensitized motor responses observed after
repeated nicotine administration (Heidbreder et al. 1995).
However, a selective µ-opioid agonist [(D-Ala2, MePhe4-
Gly5-ol) enkephalin] administered into the VTA produced
a reduction in nicotine SA in a reinstatement model
(Corrigall et al. 2000).
In humans, it has been reported that the administra-
tion of the opioid antagonist naloxone could reduce the
number of cigarettes smoked by chronic smokers (Gorelick
et al. 1988) and block the subjective pleasurable response
to smoking, thus suggesting that opioid peptides are
released during smoking and may be partially responsible
for smoking maintenance. In turn, most of the withdrawal
symptoms are not affected by naltrexone in heavy smok-
ers, although naltrexone appears to reduce the perceived
difficulty of abstaining during the first 24 h of cigarette
abstinence (Sutherland et al. 1995).
In animal models, naloxone precipitates not only an
ICSS threshold elevation in rats that received chronic
continuous nicotine but also a conditioned place aversion
(Watkins et al. 2000a, 2000b). Also, as noted above, the
physical signs induced by cessation of nicotine exposure
resemble those of the rat opiate withdrawal syndrome
(Malin et al. 1993; Watkins et al. 2000b). After chronic
nicotine exposure, a physical withdrawal syndrome
could be precipitated in rats using injections of either
nAChR or opioid receptor antagonists (Hildebrand et al.
1997, 1999; Malin et al. 1993, 1994; Watkins et al.
2000b). Also, naloxone initiates a withdrawal syndrome
in rats that was reversible by a subsequent morphine
administration (Malin et al. 1992). Similarly, the systemic
administration of an analog of neuropeptide FF, which
precipitates withdrawal symptoms in morphine-dependent
rats, also precipitated a withdrawal syndrome in nicotine-
dependent rats (Malin et al. 1996). Interestingly, meca-
mylamine-precipitated nicotine withdrawal was attenuated
by preinjection with the µ-opioid receptor agonist
morphine as well as with the selective δ-opioid agonist
TAN-67 (Ise et al. 2000). One possible hypothesis is that
chronic intermittent nicotine exposure results in a
prolonged release of endogenous opioid peptides, and
that nicotine withdrawal therefore decreases tone in
opioid receptor systems.
In addition to the behavioral evidence of an interac-
tion between nicotinic and opioid systems during with-
drawal, the hypothalamic β-endorphinergic system in
rodents was also affected during the early and late phases
of nicotine withdrawal (Table 1). For example, 4 h after
the end of a 4-week period of nicotine administration,
the expression of the pro-opiomelanocortin (POMC)
gene, the biosynthetic precursor for β-endorphin and
ACTH, was decreased in the hypothalamus (Rasmussen
1998). This effect persisted for at least 3 days following
the end of nicotine administration and after a transient
normalization, decreased again 3 weeks later (Rasmussen
1998). Therefore chronic intermittent nicotine exposure
induced a biphasic, long-lasting inhibition of POMC
gene expression in the hypothalamus. It is therefore pos-
sible that there are similar decreases in the biosynthesis
of POMC-derived peptides as well (e.g., β-endorphin).
For example, in mice, hypothalamic immunoreactive
β-endorphin is reduced 24 h and 7 days following a
chronic intermittent nicotine administration but is
increased at 2 weeks (Rosecrans et al. 1985). In contrast,
in the pituitary gland, levels of β-endorphin immunore-
activity remain unaltered during nicotine withdrawal
(Rosecrans et al. 1985). No information is currently
available on the pituitary level of POMC during early
and late nicotine withdrawal.
The expression of the enkephalins may also be modu-
lated by chronic nicotine exposure. Several rodent studies
have shown altered levels of these opioid peptides (Dhatt
et al. 1995; Pierzchala et al. 1987; Van Loon et al. 1991;
Wewers et al. 1999), but changes were interpreted mostly
as a short-term effect of the chronic nicotine regimen
rather than as a consequence of withdrawal. However,
some studies have reported that administration of nico-
tine for 2 weeks produced an increase in preproenkephalin
mRNA levels 24 h following the final injection. Prepro-
enkephalin is the peptide precursor for Leu- and Met-
enkephalins, two biologically active opioid peptides
found in both the striatum (Dhatt et al. 1995; Houdi et al.
1998) and the nucleus accumbens (e.g., Mathieu et al.
1996). Similar increases have also been described in the
hippocampus (Houdi et al. 1998). In contrast, no change
in enkephalin levels was observed in those brain regions
within the 2 h following the last nicotine injection of a
chronic regimen (Hollt and Horn 1992; Houdi et al.
1998; Mathieu-Kia and Besson 1998; Mathieu-Kia et al.
2000). This suggests that enkephalins are involved
primarily in the withdrawal syndrome (which may take
24 h to appear following the end of nicotine administra-
tion) rather than in the processes involved in ongoing
nicotine exposure.
Less information is available on the influence of nico-
tine exposure on the dynorphins, although they are a
major neurochemical substrate in the DA terminal fields,
and are altered by the effects of psychostimulant drugs
such as cocaine or amphetamine. Available studies
indicate that dynorphin synthesis is unaltered in many
regions of the rodent brain after repeated nicotine expo-
sure (Hollt and Horn 1992; Mathieu-Kia and Besson
1998; Mathieu et al. 1996; Mathieu-Kia et al. 2000), so it
is therefore premature to postulate a role for dynorphin
synthesis in the different phases of nicotine withdrawal.

Overall, a clear relationship between the endogenous
opioids and behaviors observed during nicotine cessation
is not currently evident. Early signs such as the persis-
tent drug-seeking behavior observed during saline substi-
tution, the somatic withdrawal signs, the changes in
ICSS thresholds or measure of anxiogenic responses
culminate within a 4-day period after nicotine exposure.
These behavioral observations may be associated with
changes in the β-endorphinergic or enkephalinergic
systems.
Conclusions and perspectives
Animal studies have addressed questions related to the
reinforcing effects of nicotine, and have established
some of the molecular and neuronal mechanisms under-
lying chronic nicotine use. However, our experimental
approaches for understanding nicotine addiction may not
globally model tobacco smoking behavior observed in
humans. Animal treatment protocols with long and fre-
quent access to the drug may reproduce the circadian
oscillation of nicotine concentrations in the body and the
brain of smokers. The repetitive “spiking” and the gradual
“ceiling” profile of drug use throughout the day also
needs to be incorporated in future research. In addition,
we may be entering into a new era in which smokers use
cigarettes in a more constrained pattern as a consequence
of legal restrictions and social pressure. These new
factors must be considered in the development of new
animal models of nicotine addiction. Experimental strat-
egies to model withdrawal/abstinence and relapse could
also be used to investigate the neuronal substrates that
could serve as targets for the development of novel
pharmacotherapies for nicotine addiction.
Acknowledgements This work was supported in part by the NIH-
NIDA Grants DA05130, DA00049, and DA11113. The authors are
grateful to Dr. J. Mantsch for valuable and helpful discussions
concerning many aspects of this manuscript.
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