Vol.2, No.1, 1-7 (2010
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A low dose of nicotine is sufficient to produce nicotine
withdrawal in mice
Besson Morgane1,2, Suarez Sandra1, Changeux Jean-Pierre1, Granon Sylvie1,3*
1Département de Neuroscience, Institut Pasteur, Paris, France; sylvie.granon@u-psud.fr
2Department of Experiment Psychology, Downing Site, Cambridge, UK
3Centre de Neuroscience Paris Sud, Université d’Orsay, Orsay, France
Received 12 October 2009; revised 12 November 2009; accepted 13 November 2009.
The objective of our study was to investigate
whether the chronic administration of a low
dose of nicotine can be followed by a withdrawal
syndrome at cessation of nicotine delivery. Pre-
vious studies showed various results, depend-
ing in the doses of nicotine, species, ways of
administration and behavioural paradigms, but
all emphasized a withdrawal effect on some or
all of the following spontaneous behaviours:
grooming, rearing, body shake or tremor, body
scratching, abdominal constriction, jumping.
However, it is not clear which behaviour is ex-
actly altered, as a global behavioural index is
most frequently used. This is not clear either if
anxiety modulates the behavioral expression of
withdrawal or which factors contribute to its
locomotors effect, if any. To distant-angle these
processes, we scored each of these behaviours
individually before nicotine exposure, during
continuous nicotine delivery and at cessation of
nicotine delivery after precipitated withdrawal
by mecamylamine injection. We also measured
locomotor activity and anxiety levels in the
same animals. We used a low dose of nicotine
(2.4 mg/kg/day as free base) that has been pre-
viously shown to produce nicotinic receptors
up-regulation, both in the brain and in blood
cells. With such a low dose, nicotine withdrawal
didn’t affect locomotion nor anxiety levels but
increased the number of rearing, jumping, and
marginally, body-scratching. Other behaviours,
classically considered to contribute to with-
drawal syndrome, were unaffected, e.g., groom-
ing, body or forelimb shakes. Our results show
that anxiety may be dissociated from the be-
havioural withdrawal syndrome. Also, the se-
verity of the syndrome produced by nicotine
withdrawal is qualitatively and quantitatively
different from the one induced by other drugs of
abuse and also by the one produced by nicotine
at higher doses.
Keywords: Withdrawal; Anxiety; Locomotor Activity;
Nicotinic Receptors
Nicotine is known to be an addictive substance in hu-
mans as well as in other mammals [1-3]. As such, be-
havioral studies in animal models show that nicotine
induces a withdrawal syndrome [4,5], associated with
the increased exhibition of multiple heterogeneous be-
haviors, many of which being shared by other drugs of
abuse [2,6]. These findings, however, are confounded by
two major factors: 1) in most cases, nicotine withdrawal
is not associated with the same severity of symptoms as
other drugs of abuse [6]; 2) global scores alone are not
highly informative as they may reflect the grouping of
different processes and different origins. Indeed, with-
drawal signs are constituted of exaggerated levels of
behaviours that are part of the normal behavioural rep-
ertoire of the animal, and as any behaviour, they may be
influenced by multiple parameters such as genetic strain,
individual and group level of stress, experimenter ma-
nipulation, lightning level or noise.
Authors of previous studies targeted several behav-
iours that are affected by nicotine as well as by other
addictive drugs, i.e., rearing, abdominal constriction,
grooming, scratching, chewing, cage scratching, and head
nodding and jumping [7-10], and established a global
abstinence score. In order to match with what others
previously established, we scored the same behaviours
but individually. Further, we scored the frequency of
these behaviours in the same animals, before, during and
after nicotine administration, in order to question whether
their frequency varies within and between individuals
and/or represents robust indicators of withdrawal. We
therefore expected to provide evidence regarding which
of these behaviours are specifically affected by nicotine
B. Morgane et al. / HEALTH 2 (2010) 1-7
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withdrawal. We chose to administer continuously a low
dose of nicotine (2.4 mg/kg/day, as free-base), via os-
motic mini-pumps, as it was previously shown that it is
sufficient to produce nicotinic receptor up-regulation in
the mouse [11] and to induce withdrawal syndrome in the
rat [12]. In accordance with previous studies [7,8,10,12,13],
we then used 1 mg/kg of mecamylamine to precipitate
homogeneously the withdrawal the last day of mini-pump
theoretical depletion.
Withdrawal from chronic use of nicotine also results in
increased anxiety [14,15], and reduced locomotor activity
[8,12,16-20], although these last processes were altered
either after higher doses of nicotine than the one we chose,
or in rats instead of mice. We have therefore tested the
effects of nicotine withdrawal, after the low dose admin-
istered, on locomotor activity and anxiety behaviours of
the mouse.
Experiments have been carried out following the
guidelines of the European Communities Council
(86/609/EEC). Twenty-two C57BL6/J male mice (3 to 5
months) supplied by Charles River Laboratories (France)
were housed individually upon arrival under a 12h
light-dark cycle in rooms at a controlled temperature
(21°C). All experiments were carried out during the light
phase, from 10 am to 6 pm. They were handled during
approximately ten days before the beginning of the tests.
They were slightly food deprived one week before the
start of the experiments with their weight adjusted at 90%
of their normal body weight, as the same animals were
subsequently used in a learning experiment, in order to
minimize the use of animals. However, in order to reduce
anxiety potentially induced by food deprivation, animals
were fed before the experiments.
After handling, mice were habituated 15 minutes/day
for three days to the environment (a large 50 cm X 30 cm
transparent box, containing clean bedding) in which the
behaviours were scored. Two experimenters, blind to the
drug condition of the animals, scored the behaviours on
line. Before mini-pump implantation, we first established
the baseline level of each of the following behaviours:
rearing, grooming, body shakes, body tremor and ab-
dominal constriction, jumping, scratching, forelimb
shake, chewing and head shakes. After the baseline
measurement, mini-pumps were implanted subcutane-
ously under general anesthesia (a combination of xy-
lazine, 2.5%, and ketamine, 15% in 82.5% of PBS).
Mini-pumps (Alzet) were filled with either nicotine (2.4
mg/kg/day free base) or saline delivered at a constant rate
(0.25 l/hour) for 28 days. In order to measure the effect
of chronic nicotine administration, we scored the same
behaviours a second time two weeks after mini-pump
implantation. At the last day of mini-pump delivery, i.e.,
the 28th day, mecamylamine was injected 15-20 minutes
before the beginning of the withdrawal test at a dose of 1
mg/kg, IP. The same behaviours were then scored sub-
sequently to evaluate the effects of nicotine withdrawal.
Locomotor activity was measured for 30 minutes in an
empty large open field (1m in diameter) made of white
plastic. It was situated in a room containing distal visual
cues with light level set between 80 and 100 Lux and was
placed under a camera connected to a video-track system
that allows the discrimination of navigatory -speed >
11.8cm/sec- and exploratory movements -speed <
6.8cm/sec- [17]. It has been shown that rodents sponta-
neously avoid the center of a large open area which is more
brightly illuminated than the periphery [21]. We therefore
used the number of visits and time spent in the center as an
index of anxiety during free exploratory activity. The
baseline level of anxiety is altered by novelty [22]. There-
fore, in order to avoid the alteration of the anxiety level
generated by the first visit of a new environment, we
conducted exploratory experiments in distinct groups of
mice under the chronic administration of nicotine or saline
and during withdrawal of nicotine or saline.
Each behavior was analyzed using repeated measures
analysis of variance (ANOVAs) with “Drug condition” as
the main within-subject factor, with 3 levels (before im-
plantation, under chronic treatment and withdrawal), and
“treatment” (with 2 levels, saline and nicotine) as the
main between-subjects factors. Upon significant main
effect (i.e., for p<0.05), data was further analyzed with
paired t-tests.
Statistical analysis revealed a significant effect of the
main within-subject factor, drug condition, for rearing
(F(2,40)=15.38, p<0.0001), jumping (F(2,40)=3.98, p<0.026),
body-scratching (F(2,40)=5.05, p=0.01), grooming (F(2,40)=
3.23, p=0.05) and forelimb shakes (F(2,40)=12.23, p<
0.0001), suggesting that, individually, each of these pa-
rameters were altered either by the treatment and/or the
repetition of the test. We also observed a significant in-
teraction drug condition X treatment for rearing (F(2,40)
=3.96, p=0.027), suggesting that nicotine and saline
treatment produced a different effect on rearing. By con-
trast, no significant effect of drug condition and no in-
teraction drug condition x treatment were observed for
abdominal constriction (respectively, F<1 and F(2,40)=1.61,
NS) suggesting that this variable was not altered by the
drug condition and, therefore, may not contribute sig-
nificantly to the withdrawal syndrome.
When measured under chronic treatment, rearing
(t=-0.86, p=0.4, df=20) and jumping (t=0.34, p=0.74,
df=20) levels were similar in animals receiving saline and
those receiving nicotine, making both variables unaf-
fected by the chronic administration of nicotine, as illus-
trated in Figure 1. Grooming was the only behaviour that
showed a significant main effect of group (F(1,20)=7.44,
p=0.013) and a significant main effect of drug condition
(F(2,40)=3.23, p=0.05) with no significant interaction (F<1,
NS), suggesting that the drug condition was identical for
the group receiving saline and the one receiving nicotine.
It further suggests that the group effect (i.e. nicotine effect)
was not dependent of the drug condition, i.e., both groups
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Figure 1. Quantification of spontaneous behaviours affected by chronic administration of nicotine and nicotine with-
drawal precipitated by injection of mecamylamine. Rearing, jumping, scratching, grooming and forelimb shakes were
scored before mini-pump implantation (baseline), under chronic nicotine (white) or saline (black) treatment, and the last
day of mini-pump delivery, 20 min after mecamylamine injection (withdrawal). * indicates a significant difference be-
tween animals under saline and those under nicotine.
may show different levels of grooming before mini-pump
implantation. Post-hoc tests confirmed that the level of
grooming was marginally different between the saline and
the nicotine groups at baseline condition (t=-1.95,
p=0.065, df=20) and was significantly different under
chronic treatment (t=-2.38, p=0.027, df=20). These results
suggest that nicotine had no effect by itself on grooming
but that both groups, analysed by experimenters blind to
the drug condition of the animals, were different regard-
ing this parameter from the beginning of the experiment.
Body-scratching was marginally affected by the chronic
drug treatment (t=-2.05, p=0.054, df=20). As illustrated in
Figure 1, and confirmed by paired t-tests, animals re-
ceiving saline showed significantly less body- scratching
levels when tested on baseline than when tested under
mini-pumps (p=0.026) whereas animals receiving nico-
tine did not show different level of body- scratching be-
tween the two testing conditions (p=1.0). This suggests
that the repetition of the test affected only animals that
were not under nicotine treatment.
Forelimb shakes were unaffected by nicotine admini-
stration as the number of paw tremor recorded was not
significantly different between animals receiving saline
and those receiving nicotine under chronic treatment
(t=0.17, p=0.87, df=20).
Post-hoc tests confirmed that the levels of rearing
(t=-7.03, p<0.0001, df=10), jumping (t=-2.33, p=0.042,
df=10), body-scratching (t=-2.14, p=0.058, df=10) and
forelimb shakes (t=-2.58, p=0.027, df=10) were signifi-
cantly different under nicotine administration and during
withdrawal. The levels of rearing, jumping and body
scratching didn’t change from chronic treatment to with-
drawal condition in saline animals (respectively: t=0.4,
p=0.7, NS; t=0.25, p=0.81, NS and t=-0.99, p=0.35, NS),
suggesting that these behaviours were altered specifically
by nicotine withdrawal, as illustrated in Figure 1 Fore-
limb shakes were significantly altered in mice under
chronic administration of saline (paired t-test conducted
for chronic condition versus withdrawal condition, t=-2.7,
p=0.022, df=10), suggesting that this behaviour was
affected by mecamylamine administration but not by
nicotine withdrawal. Post-hoc tests showed that nicotine
withdrawal did not affect grooming (t=-1.43, p=0.18,
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Figure 2. Exploratory and navigatory activity recorded in the circular open field for 30min during chronic treatment
(A) and during withdrawal (B). No significant difference was found between animals under saline (black) and those
under nicotine (white).
Navigation and exploration were not affected by the
chronic administration of nicotine, as illustrated in Fig-
ure 2A ANOVAs confirmed that there was no treatment
effect on navigation nor on exploration (both Fs<1, NS).
For both types of behaviour, there was a significant effect
of habituation (for navigation: F(5,85)=44.6, p<0.0001; for
exploration: F(5,85)=31.85, p<0.0001) and no significant
interaction treatment X habituation (both Fs<1, NS)
suggesting that subjects receiving saline as well as those
receiving nicotine showed normal habituation.
Navigation and exploration (Figure 2) were not statis-
tically different after withdrawal in saline and in nicotine
animals, as there was no treatment effect neither for
navigation (F(1,12)=1.05, NS) nor for exploration (F<1,
NS). Within 30 minutes, there was a significant habitua-
tion for both navigation (F(5,60)=57.96, p<0.0001) and
exploration (F(5,60)=25.02, p<0.0001) but no significant
interaction treatment X habituation for either navigation
(F(5,60)=1.1, p=0.37, NS) or exploration (F<1, NS). These
results showed that the levels of exploratory and navi-
gatory activity as well as habituation were not affected by
nicotine withdrawal.
The chronic administration of nicotine didn’t affect the
number of entries in the centre (data not shown, ANOVAs
for drug effect: F(1,17)=2.45, NS) but produced a trend to
reduce the time spent in the centre of the arena (Figure
3A, ANOVAs for drug effect: F(1,17)=4.33, p=0.053),
suggesting that, in an unfamiliar environment, chronic
nicotine administration tends to increase anxiety level.
The total number of entries in the centre (data not
shown) and the time spent in the centre of the open field
in 30 minutes (Figure 3B) were not different after with-
drawal between saline and nicotine animals, as confirmed
by ANOVAs (no drug effect for number of entries: F<1,
NS; no drug effect for time in the centre: F<1, NS). These
results showed that the level of anxiety was not affected
by nicotine withdrawal in an unfamiliar environment.
Our present results demonstrate that only rearing,
jumping and body-scratching reflect specifically nicotine
withdrawal syndrome in mice, when nicotine dependence
is produced by the continuous administration of a low
dose i.e., 2.4mg/kg/day. This dose has been shown to
induce a significant up-regulation of nicotinic receptors
both in the blood and in the brain [11]. We find that in
these conditions nicotine withdrawal affects neither
anxiety nor locomotion. Previous studies have used sig-
nificantly higher doses, i.e., up to ten times higher, that
induced withdrawal signs of different nature than the one
we observed in the present study but that also increased
anxiety level [9,14,15]. Interestingly, when using a dose
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Figure 3. Time spent in the centre of the brightly illuminated open field over one single 30-minute session during chronic
treatment (A) and during nicotine withdrawal (B). Under chronic nicotine, mice tended to decrease the time spent in the
centre of the open field, as compared to animals receiving saline (A). No significant difference was found between ani-
mals receiving saline (black) and those receiving nicotine (white) during withdrawal (B).
in a range similar to our, but excluding rearing and
jumping from their scores, Damaj and collaborators [14]
did not find any withdrawal signs or anxiety alteration.
Therefore, in agreement with previous studies using a
large range of nicotine doses, our present results provide
evidence that a low dose of nicotine given continuously
also induces an increase in the frequency of some specific
behaviour. Using a low dose of nicotine, we were able to
show dissociation between anxiety and other behavioural
processes that may influence the general withdrawal
syndrome. This dissociation suggests that withdrawal
signs may not be exclusively due to an increase in anxiety
levels after nicotine abstinence. It must be noticed that
our animals were under a slight food deprivation schedule
and, although they were fed before behavioural recording,
we cannot exclude that chronic food deprivation has
modified the effects of nicotine withdrawal. We con-
ducted experiments (unpublished results) showing that a
slight chronic food deprivation doesn’t alter by itself
navigatory and exploratory processes. These experiments
do not provide evidence that food deprivation does not
interfere with the nicotine exposure, for example by in-
creasing anxiety levels. Such data are not yet available, to
our knowledge.
Rearing behaviours have been shown to be sensitive to
manipulations of the dopaminergic system [23]. Hilde-
brand and collaborators [13] also showed in nicotine-
dependent rats that intra-Ventral Tegmental Area injec-
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tion of mecamylamine induced a rearing frequency modi-
fication with a dose of nicotine similar to our dose range.
Therefore, it is possible that chronic nicotine administra-
tion followed by precipitated withdrawal created a deficit
in cholinergic transmission which, in turn, reduced do-
pamine (DA) release, leading to an increased level of
rearing. Microdialysis studies indeed showed that in
nicotine-dependent rats, precipitated withdrawal leads to
a decrease in DA release in the nucleus accumbency and
in the prefrontal cortex [24,25]. Considering the role of
the DA system in addiction [1], it is therefore not sur-
prising that behaviours that are influenced by its modu-
lation are particularly affected during withdrawal. Fore-
limb shakes are generally considered as a behavioural
manifestation associated with drug withdrawal [8,26].
Our results showed that their frequency was affected by
mecamylamine administration but not by nicotine with-
drawal, as it was observable also in mice that were ad-
ministered saline chronically. Previous studies [14,27]
showed that this measure as well as some other signs are
affected by hexamethonium or chlorisondamine, nico-
tinic antagonists which penetrate poorly the blood-brain
barrier. Therefore, our data, along with previous ones [19]
suggests that forelimb shakes are from peripheral origin
and cannot be considered as a centrally-mediated with-
drawal sign. We further show here that some of the be-
haviours usually recorded as part of a withdrawal syn-
drome, i.e., grooming, may be affected by the repetition
of testing, but not by the nicotine treatment or withdrawal.
It is furthermore noticeable that a baseline difference
between groups (Figure 1), uncorrected as the experi-
menters were blind to the animals’ treatment, remains
observable for weeks, despite the habituation of the
animals. This suggests that grooming is a behaviour that
varies strongly between individuals, reinforcing the in-
terest of longitudinal studies that allow baseline meas-
urements. We also showed that body scratching was af-
fected by nicotine administration and, only in animals
that received nicotine, by withdrawal. Although this ef-
fect is statistically evidenced, it must be noticed that in
absolute numbers, it is not highly represented in our data
and should therefore be confirmed, despite the fact that it
is classically associated with drug withdrawal [8,10,20,27].
Together with grooming data, scratching data emphasized
the necessity to give baseline levels of such spontaneous
behaviours when scoring drug effects.
In the open field, our data showed that mice under
chronic administration of nicotine tend to spend less time
in the centre of the arena, suggesting that, in an unfamiliar
environment, chronic nicotine administration tends to
increase anxiety. Our results also show that nicotine
withdrawal, at a low dose, had no effect on anxiety when
the anxiogenic environment was not familiar. This result
is compatible with the one of other authors who compared
the withdrawal effect after different doses of nicotine on
anxiety [14].
Locomotor activity was affected neither by chronic
nicotine exposure, nor by withdrawal. It is noticeable that,
in rats, a similar dose of nicotine induced a temporary
decrease of locomotor activity that was observable be-
tween 16 to 24 hours after mini-pump removal [6,12], but
not in mice after pharmacological precipitation [28]. It is
not possible to conclude firmly from experimental data
obtained in different species (rats versus mice) and with
two different procedures (mini-pump removal versus
precipitation). Indeed, it is known that the sensitivity to
nicotine is different in rats and mice [29]. Also, it is pos-
sible that mini-pump removal, that allows enough time
for producing alteration in striatal DA concentration [12],
produces a higher impact on locomotor activity than
pharmacological precipitation, via DA mechanisms.
In conclusion, our present results support the idea that a
continuous administration of low dose of nicotine, fol-
lowed by pharmacological precipitation of withdrawal, is
sufficient to produce a withdrawal syndrome in the mouse
represented by increased levels of rearing and jumping.
With such a low dose, nicotine withdrawal didn’t affect
locomotion nor anxiety levels. Other behaviours, con-
tributing to nicotine withdrawal after higher doses of
nicotine, were unaffected. Therefore, in spite of the fact
that anxiety may produce some of the behaviours associ-
ated with nicotine withdrawal, other behaviours, unre-
lated with anxiety can also be affected. These results can
be discussed in terms of a relatively dissociable role of
nicotinic receptors in the reward versus somatic de-
pendence systems.
The future determination of whether these behaviours
rely on specific neurotransmitter systems or brain struc-
tures is expected to complement the current therapeutical
proposal of the withdrawal syndrome [30, for review].
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