Behavioural Brain Research 167 (2006) 150155

Research report

Context is a trigger for relapse to alcohol

Isabella Zironi a, , Costanza Burattini a , Giorgio Aicardi a,b , Patricia H. Janak c
a

Department of Human and General Physiology, University of Bologna,

Via San Donato 19/2, 40127 Bologna, Italy
b Interdepartment Center Luigi Galvani for the study of Biophysics, Bioinformatics and Biocomplexity,
University of Bologna, Via San Giacomo 12, 40126 Bologna, Italy
c Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, 5858 Horton St. Suite 200,
Emeryville, CA 94608, USA
Received 9 December 2004; received in revised form 31 August 2005; accepted 3 September 2005
Available online 26 October 2005

Abstract
The environment in which alcohol consumption occurs may trigger later relapse in alcohol abusers. In this study, we tested whether an alcoholassociated environment would induce alcohol-seeking behavior. Male rats were trained to lever press for oral alcohol reinforcement in a distinctive
context. Responding was then extinguished in a context with different olfactory, visual and tactile properties. Placement of the rats back into the
original context in which they self-administered alcohol induced, in the absence of alcohol availability, a significant increase in lever press responding
on the alcohol lever as compared to extinction levels of responding. The ability of the alcohol context to support alcohol-seeking behavior was
maintained over 3 weeks, with no significant diminution. A second group of rats was trained to lever press for sucrose reinforcement; this group also
demonstrated context-dependent reinstatement, although the degree of reinstatement decreased over repeated tests, returning to extinction values
after 3 weeks. These findings indicate that contextual conditioning has a long-term impact on ethanol-seeking behavior after ethanol withdrawal.
This animal model may be useful to study the neural mechanisms underlying relapse induced by ethanol-associated contexts in humans.
2005 Elsevier B.V. All rights reserved.
Keywords: Alcohol; Context

1. Introduction
Relapse to drinking after prolonged abstinence is a major
clinical problem in alcohol addiction. Although re-exposure to
alcohol itself can induce relapse, other factors including exposure to cues associated with alcohol use can induce craving and
mediate relapse in humans [22,23,29,34] and can cause resumption of alcohol-seeking behavior in laboratory animals even after
prolonged withdrawal periods (for review, see [20]). For example, discrete conditioned stimuli such as tones, lights, or smells
associated with ethanol delivery reinstate extinguished responding at the lever that previously delivered alcohol [2,3,9,18,28].
However, the environment in which alcohol is habitually
consumed is characterized by several discrete cues, which
altogether provide a complex multimodal contextual stimulus,
which appears effective in enhancing craving and motivation for

Corresponding author. Tel.: +39 051 2095632; fax: +39 051 2095629.
E-mail address: zironi@biocfarm.unibo.it (I. Zironi).

0166-4328/$ see front matter 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbr.2005.09.007

ethanol-seeking behavior in humans. For example, the desire

to drink alcohol is enhanced by exposure to alcohol-suggestive
contextual cues [25]. In addition, abstinent alcoholics report that
specific environments, such as bars and parties, elicit craving for
alcohol [22]. It has been shown that the context can also modulate
other behavioral effects of drugs of abuse, such as the sensitization to psychomotor stimulant effects of amphetamine [1,32],
and may have a stronger impact than discrete drug-associated
cues [12]. Recently, this kind of investigation has been carried
out in an animal model for relapse triggered by intravenous drugassociated environments [13]. In this model, subjects acquire an
i.v.-drug self-administration habit in a distinctive context, and
then undergo a period of extinction in a second distinctive context during which the drug is no longer available. When the
subjects are placed once again into the drug-associated context,
drug seeking is robustly renewed.
In the present work, to investigate the influence that the physical context might play on relapse to ethanol-seeking behavior,
rats were trained to self-administer an ethanol solution in a
distinctive context. Following extinction of ethanol or sucrose

I. Zironi et al. / Behavioural Brain Research 167 (2006) 150155

151

responding in a context with different olfactory, visual and tactile properties, the effect of re-exposure to the context that was
associated with reward availability was tested at different time
intervals in the absence of reward. Clinical reports indicate
that environmental stimuli associated with alcohol consumption may elicit drug-seeking behavior after a long period of
abstinence [14,29]. Accordingly, animal studies have demonstrated that discrete cues can induce alcohol-seeking behavior
after long-term abstinence [4,8]. Here, we tested the effect of
the alcohol-associated context on alcohol-seeking behavior up
to 3 weeks after extinction.
Conditioning to contextual versus discrete cues seems to
be mediated by different, although partly overlapping, neural
systems [30]. In particular, numerous studies support a necessary role for the hippocampus in conditioning to contextual
cues [11,17,19,24,33,36]. Ethanol has been shown to inhibit
spatial learning/cognition, as well as hippocampal spike firing,
NMDA-dependent synaptic transmission and long-term potentiation [15,21,27,35]. Animals in the current study were waterrestricted to encourage ethanol intake to test if the context may
influence relapse at levels of ethanol consumption that are likely
to alter hippocampal spatial function. A second group of subjects trained to self-administer sucrose provided a control for
the pharmacological effects of ethanol and a test of the reward
generality of the model.

2.3. Procedure

2. Methods

2.4.1.2. Reinstatement test

Eight and six randomly chosen animals from the ethanol and sucrose groups,
respectively, were tested for operant response reinstatement with no reward
availability in the acquisition context (context A) the day after the last extinction
session, 2 and 3 weeks later. Animals were also tested in the extinction context
(context B) 15 days after the last extinction session.

2.1. Subjects
All procedures were approved in advance by the Gallo Center Institutional
Animal Care and Use Committee. Twenty-two male LongEvans rats (Harlan)
weighing 150160 g at arrival were singly housed in a climate-controlled room
maintained on a 12 h light/dark cycle, lights on at 07:00 h, with food and water
available ad libitum except as noted below. Subjects were randomly divided
into two groups: the ethanol group, which received ethanol pre-treatment (two
bottle preference paradigm; see below) and the sucrose group which received no
pretreatment. Four weeks later, both groups of animals underwent 24 h of water
restriction before the first operant conditioning session. From this day onward,
subjects received 1 h free access to water in the home cage. When the delay
between sessions was longer than 3 days, water restriction started 24 h before
the experimental session.

2.3.1. Two bottle preference paradigm

To accustom subjects to the taste and pharmacological effects of ethanol,
the ethanol group received access for 3 days to a solution of 10% (v/v) ethanol
in tap water, followed by 3 weeks of simultaneous access to both 10% ethanol
in tap water and tap water alone. Amounts of ethanol and water consumed, and
body weights, were measured daily.

2.4. Operant response paradigm

Subjects in the ethanol (n = 12) and sucrose groups (n = 10) were trained to
self-administer a solution of either ethanol (10%, v/v) or sucrose (10%, g/v)
on a continuous fixed-ratio-1 schedule of reinforcement (FR-1), in response to
lever press. The experiment consisted of three phases: acquisition/maintenance
in either the first or the second context (random and counterbalanced assignment,
referred to as context A), extinction in the other context (referred to as context B)
and reinstatement in the acquisition/maintenance context (A), in the extinction
context (B) or in a novel context (third context, referred as context C). At the
beginning of all sessions the house light was switched on and the retractable
lever appeared in the box.
2.4.1.1. Acquisition/maintenance and extinction
Both groups were initially trained to lever press in an over-night session
in context A. Operant responses were reinforced with the delivery of 0.1 ml of
either ethanol or sucrose, available in the reward cup for 3 s. Rats next underwent
1520 daily 60 min acquisition/maintenance sessions in context A. At the end
of this phase, operant responses were extinguished in context B by eliminating
reward delivery (46 daily sessions).

2.4.1.3. Novelty test

The remaining four animals from each group (ethanol and sucrose) were
tested for novelty effects on operant response reinstatement by exposing them
to context C 24 h after the last extinction session.
2.4.1.4. Data analysis
Total lever presses and rewards given during the 1 h sessions were measured.
A Students t-test or a repeated measures one-way ANOVA followed by post hoc
LSD tests were performed as indicated. Results are presented as means S.E.M.

2.2. Apparatus

3. Results

Standard sound-attenuated operant conditioning chambers (30.5 cm

24.1 cm 21 cm, Med Associates Inc., Georgia, VT, USA) were equipped with
a retractable lever located in the center of the left wall, and a white house light
(28 V, 100 mA light) positioned on the top of the same wall. Rewards were
delivered via a 0.1 ml dipper system that when activated allowed access to fluid
reward in a 5 cm 5 cm 3.5 cm recess that was 11 cm to the right of the lever.
To provide three different contexts, boxes were manipulated in their olfactory,
visual and tactile properties. The first context consisted of a clear acrylic ceiling,
back wall and front door, with side walls of aluminum, and a floor of stainless
steel tubes 4.8 mm in diameter and spaced 1.6 cm from center-to-center. A green
pine-scented air freshener on the back wall provided a strong olfactory and visual
cue. For the second context, the ceiling, front door and back wall were covered
by black paper. A smooth semitransparent sheet of Plexiglas covered the grid
floor and a red strawberry-scented air freshener was posted on the door wall.
The third context had black and white diagonally striped walls (ceiling, front
door and back wall), a rough semitransparent sheet of Plexiglas covering the grid
floor, and 1% acetic acid solution sprayed on the bedding underneath the grid.

3.1. Two bottle preference paradigm

Subjects in the ethanol group (n = 12) consumed daily an
average of 3.13 0.57 g/kg during the 3 days of forced access
to ethanol solution, 0.36 0.07 g/kg the first week of free choice
between ethanol solution and water, and 0.92 0.23 g/kg the last
week.
3.2. Operant response paradigm
3.2.1. Acquisition/maintenance and extinction
Fig. 1 shows the mean number of lever presses and rewards
given during each session of acquisition/maintenance (in context A) and extinction (in context B) phases, for all the ethanol

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I. Zironi et al. / Behavioural Brain Research 167 (2006) 150155

Fig. 1. Mean number of lever presses and rewards given during each session of acquisition/maintenance (context A) and extinction (context B) phases, for ethanoltrained (n = 12) and sucrose- trained (n = 10) subjects. * P < 0.05, ** P < 0.01, as compared to the last acquisition/maintenance session (Students t-test).

(n = 12) and sucrose (n = 10) trained subjects. The ethanol group

animals consumed an average of 1.31 0.07 g/kg per 1 h acquisition/maintenance session (range, 0.941.61). During extinction in context B, there was a gradual decrease in the number
of operant responses. Compared to the final day of the acquisition/maintenance phase, mean responding in the ethanol group
was significantly (P < 0.01, Students t-test) lower by the second
extinction session, while in the sucrose group the decrease was
already significant (P < 0.05, Students t-test) by the first session.
3.2.2. Reinstatement test
Twenty-four hours after the last extinction session, two
groups of animals (ethanol, n = 8; sucrose, n = 6) underwent
the first reinstatement test in context A with no reward delivery (reinstatement test, day 1, Fig. 2). Two and 3 weeks later,
both groups were tested again for reinstatement in context A
(reinstatement test, days 14 and 21, Fig. 2). Both groups were
also tested in context B 15 days after the first reinstatement
test (reinstatement test, day 15, Fig. 2). Placement in context
A increased the mean number of lever presses for both the
ethanol and the sucrose group, while responding in context
B remained at extinction levels (Fig. 2). ANOVA of leverpress responding during the last extinction session and all four
reinstatement sessions revealed significant context-dependent
response reinstatement effects for both ethanol and sucrose
groups (F4,28 = 8.55, P < 0.0001 and F4,20 = 12.16, P < 0.00001,
respectively). Post hoc tests revealed that both groups significantly increased the number of operant responses when tested
in the acquisition context (context A) 1 day after the extinction in context B (extinction versus reinstatement test, day 1,
P < 0.005 for ethanol and P < 0.0001 for sucrose), as well as
2 weeks after the first reinstatement (extinction versus reinstatement test, day 14, P < 0.0005 for ethanol and P < 0.01 for
sucrose). Placement back into context A 3 weeks later did not

result in significantly increased responding in the sucrose group

relative to the first extinction (P = 0.19), but did result in significantly increased responding in the ethanol group (P < 0.005).
For both groups, responding in context B, tested 15 days after
the first reinstatement was not different from the final extinction day in context B (all Ps > 0.05). In addition, responding on
all reinstatement days was significantly greater than that in the
second context B exposure 15 days after extinction (reinstatement test, day 15 versus reinstatement test, days 1, 14 or 21, all
Ps < 0.05).
The stability of the response reinstatement in context A
was also tested. Analysis of the three reinstatement sessions
in context A revealed a time-dependent effect on responding
for the sucrose group (F2,10 = 10.10, P < 0.004). Specifically,
responding was higher during the first reinstatement session as
compared to both the second (reinstatement test, day 14) and
third (reinstatement test, day 21) session for the sucrose group
(P < 0.05 and P < 0.005, respectively). In contrast, there was no
effect of time for the ethanol group (F2,14 = 0.17 ns), indicating
that responding was not different across the three reinstatement
tests.
3.2.3. Novelty test
Twenty-four hours after the last extinction session, subjects
trained to self-administer ethanol (n = 4, Fig. 3A) and sucrose
(n = 4, Fig. 3B) were tested in context C, a novel environment, to
verify whether exposure to a context different from the extinction
context is sufficient to increase operant responding. As shown
in Fig. 3, exposure to the novel environment increased the mean
number of lever presses for both ethanol and sucrose groups.
However, a comparison of responding during exposure to the
novel environment to that on the last extinction session revealed
a significant difference only for the sucrose group (Students
t-test, P < 0.05).

I. Zironi et al. / Behavioural Brain Research 167 (2006) 150155

Fig. 2. Mean number of lever presses emitted by (A) the ethanol-trained subjects
(n = 8) and (B) the sucrose-trained subjects (n = 6) in the extinction context B
(white columns) and in the acquisition/maintenance context A (black and gray
filled columns for ethanol and sucrose group, respectively). Twenty-four hours
after the last extinction session (extinction), animals underwent the first reinstatement test in context A (reinstatement test, day 1). Two and 3 weeks later,
both groups were tested again for reinstatement of the operant response in context A (reinstatement test, days 14 and 21), and in context B 15 days after the
first reinstatement test (day 15). No reward was delivered for any of the tests.
* P < 0.01 as compared to extinction and # P < 0.01 as compared to reinstatement
test, day 15 (post hoc LSD test).

4. Discussion
The results of this study indicate, for the first time to our
knowledge, that the environmental context can induce relapse
to ethanol seeking behavior after operant response extinction
and in the absence of ethanol availability. Memory for the
ethanol-associated context was specific, as placement into the
non-ethanol extinction context did not induce ethanol-seeking.
In addition, memory for the ethanol-associated context was per-

153

sistent, lasting up to 3 weeks, the final time point tested. This

result suggests that pharmacological effects of self-administered
ethanol are sufficient to produce long-lasting modification of
animals behavior, leading to relapse phenomena even after prolonged abstinence.
The second group of subjects trained to self-administer
sucrose provided an interesting control for the effects of ethanol.
In particular, we found that subjects trained to lever press for
sucrose in a distinctive context, and then extinguished in a different context, reinstate lever press responding when placed
back into the sucrose-associated context. However, the degree of
reinstatement decreased over repeated tests, returning to extinction values after 3 weeks. These findings indicate that rewardassociated contexts can induce seeking behavior for both drug
and natural rewards, but this behavior is long lasting only for
drug rewards. Similarly, the ability of cocaine-associated cues
to reinstate responding lasts far longer than cues associated with
a non-drug reinforcer [10,16].
It might be proposed that, after a prolonged time of no
reward availability in either context, animals are no longer able
to remember which environment was associated with reward,
and that the responding at test reflects spontaneous recovery of
the extinguished responding (for review, see [31]). We, therefore, tested the subjects in the extinction context 2 weeks
after the first extinction session. The non-significant effect
of the extinction context on operant response reinstatement
for both the ethanol- and sucrose-trained groups confirmed
that animals are able to recall the specific association of one
context with previous reward availability over a considerable
time.
We also saw a difference in the effect of a third novel context
between reward substances. Specifically, the novel environment
induced significant reinstatement in sucrose-trained subjects, but
not in ethanol-trained subjects. This finding indicates that the
reward-paired context may be particularly critical for reinstating ethanol-seeking behavior, although the small sample size for
this manipulation precludes firm conclusions. Interestingly, this
finding agrees with Bossert et al. [5] who found that a novel
context did not reinstate responding for heroin. On the other
hand, studies of contextual control of responding for appetitive
reinforcers after extinction have found that conditioned responding is increased by a novel context (for review, see [7]). Hence,
contextual control over responding for drug and alcohol unconditioned stimuli may be stronger than for natural rewards, like
sucrose.
We restricted the water intake of the experimental subjects
to ensure high ethanol intakes. Ethanol doses such as those
consumed herein (1.31 0.07 g/kg) are reported to alter hippocampal spatial function. For instance, Melia et al. [26] found
that 1.01.5 g/kg of ethanol administered before training disrupts contextual fear conditioning. In our experiments, subjects
showed significant and long-lasting reinstatement to the context,
indicating that regular consumption of ethanol at these doses
does not impact the formation of the contextethanol association. These findings are in agreement with Boulouard et al. [6]
who found that chronic exposure to ethanol produced tolerance
to the spatial memory impairing effects of acute ethanol.

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I. Zironi et al. / Behavioural Brain Research 167 (2006) 150155

Fig. 3. Mean number of lever presses emitted by (A) the ethanol-trained subjects (n = 4) and (B) the sucrose-trained subjects (n = 4) in the extinction context B (white
columns) and in the novel context C (black and gray columns for the ethanol and the sucrose group, respectively). Twenty-four hours after the last extinction session
(extinction), animals underwent a reinstatement test in context C (novelty test) with no reward delivery. * P < 0.05 (Students t-test).

Previously, we [28] and others [2,9,18] found that conditioned

and/or discriminative cues can reinstate ethanol-seeking behavior after extinction. Hence both discrete cues and environmental
contexts that are associated with ethanol availability can induce
ethanol-seeking behavior after a period of abstinence. In the
current study as well as in our previous study [28], we found
that animals trained to self-administer sucrose demonstrated a
similar effect of context or discrete cues, respectively, on reinstatement of sucrose-seeking, indicating that the conditioning
processes engaged during ethanol self-administration are general processes involved in conditioned associations with reward.
However, here we found that the ability of ethanol to reinstate
the seeking behavior was more persistent over time compared
to sucrose, supporting the view of a peculiar effect of ethanol on
memory processes involved in addictive behavior.
Taken together, present findings support the notion from clinical observations that environmental context can impact relapse
to alcohol seeking behavior [23,29]. Thus, this animal model
may be useful to study the neural mechanisms underlying this
phenomenon.

[5]

[6]

[7]
[8]

[9]

[10]

[11]
[12]

Acknowledgements
This work was supported by funding from the State of California for medical research on alcohol and substance abuse through
the University of California in San Francisco. I.Z. and C.B. were
partly supported by fellowships from the University of Bologna
(Italy). I.Z. was also supported by a scholarship from the Rotary
Foundation (Rotary International).

[13]
[14]

[15]

[16]

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