Pharmacology, Biochemistry and Behavior 166 (2018) 35–41

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Pharmacology, Biochemistry and Behavior

journal homepage: www.elsevier.com/locate/pharmbiochembeh

Environmental enrichment facilitates cocaine abstinence in an animal T

conflict model☆
⁎
Scott Ewinga, Robert Ranaldia,b,
a
The Graduate Center of the City University of New York, 365 Fifth Avenue, New York, NY 10016, USA
b
Department of Psychology, Queens College, City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367, USA

A R T I C L E I N F O A B S T R A C T

Keywords: In this study, we sought to discover if housing in an enriched environment (EE) is an efficacious intervention for
Environmental enrichment encouraging abstinence from cocaine seeking in an animal “conflict” model of abstinence. Sixteen Long-Evans
Cocaine abstinence rats were trained in 3-h daily sessions to self-administer a cocaine solution (1 mg/kg/infusion) until each de-
Intravenous self-administration (IVSA) monstrated a stable pattern of drug-seeking. Afterward, half were placed in EE cages equipped with toys, ob-
stacles, and a running wheel, while the other half were given clean, standard laboratory housing. All rats then
completed daily 30-min sessions during which the 2/3 of flooring closest to the self-administration levers was
electrified, causing discomfort should they approach the levers; current strength (mA) was increased after every
day of drug seeking until the rat ceased activity on the active lever for 3 consecutive sessions (abstinence). Rats
housed in EE abstained after fewer days and at lower current strengths than rats in standard housing. These
results support the idea that EE administered after the development of a cocaine-taking habit may be an effective
strategy to facilitate abstinence.

1. Introduction
Despite advances in the prevention and treatment of drug addiction,
cocaine use remains stable and problematic in the US; recent data es-
timate that 1.87 million Americans have used cocaine in the last month,
and 867,000 met DSM-IV-TR criteria for a cocaine-specific stimulant
use disorder in 2016 (APA, 2000; Center for Behavioral Health Statistics
and Quality, 2017). Many struggle to abstain from cocaine and relapse
is common, as cravings often overshadow the immediate, legal, and
social costs, medical risks (e.g., Fonseca and Ferro, 2013; Maraj et al.,
2010; Riezzo et al., 2012), and the possibility of neuropsychological
injury (Buttner, 2012; Spronk et al., 2013). Psychological and phar-
macotherapeutic interventions provide relief from craving in some
users, but a deeper understanding of the contribution of environmental
factors to cocaine dependence could open doors to more effective
treatments.
While it is widely known from studies of human addicts that ex-
posure to negative or stressful stimuli can intensify addictive behaviors
and trigger drug relapse, decades of research with rodents have de-
monstrated myriad benefits induced by access to positive, enriched
environments (EE). EE studies have varied greatly in methodology,
including types of enrichment, duration of exposure, and the age,
breed, and gender of rodent subjects, but most involve a larger habitat
when compared to standard housing and interaction with novel objects
and/or social cohorts (for a review, see Simpson and Kelly, 2011).
Housing in EE cages has been shown to reduce anxiety (Leal-Galicia
et al., 2007; Pena et al., 2009; Qian et al., 2008), responsivity to stress
(Fox et al., 2006; Segovia et al., 2009), depressive phenotypes and
endogenous markers of depression (Brenes et al., 2009, 2008; Fox et al.,
2006; Koh et al., 2007; Segovia et al., 2009), and improve cognitive
functioning, such as learning and memory (for a review, see Simpson
and Kelly, 2011).
In studies specific to the effects of EE on cocaine exposure, housing
in EE (when compared to standard housing) has often been shown to
significantly reduce behavioral responses to cocaine and the incidence
of addiction-related behaviors. These phenomena are observed using a
variety of behavioral paradigms, including quantification of cocaine-
induced locomotor activity (Bezard et al., 2003; Galaj et al., 2017;
Solinas et al., 2008, 2009), conditioned place preference (CPP; Galaj
et al., 2017; Green et al., 2010; Solinas et al., 2008; Solinas et al., 2009),
and intravenous self-administration (IVSA) studies, which may provide
more direct insight into motivations behind cocaine-seeking (Chauvet
et al., 2009; Gipson et al., 2011; Green et al., 2010; Peck et al., 2015;
Puhl et al., 2012; Ranaldi et al., 2011; Thiel et al., 2011, 2009). The use

☆
This research was funded by an internal grant from the Professional Staff Congress of City University of New York (PSC CUNY) (PSC 67098-00 45).
⁎
Corresponding author at: Psychology Department, Queens College, 65-30 Kissena Blvd., Flushing, NY 11367, USA.
E-mail address: Robert.Ranaldi@qc.cuny.edu (R. Ranaldi).

https://doi.org/10.1016/j.pbb.2018.01.006
Received 2 October 2017; Received in revised form 29 January 2018; Accepted 30 January 2018
Available online 31 January 2018
0091-3057/ © 2018 Elsevier Inc. All rights reserved.
S. Ewing, R. Ranaldi
of EE as a protective tool (i.e., pre-cocaine exposure) for prevention of
cocaine-related behaviors has yielded inconsistent results (for a brief
review, see Galaj et al., 2017); rearing in EE or short-term, pre-cocaine
EE exposure has been shown to likewise inhibit (e.g., Gipson et al.,
2011; Solinas et al., 2009), enhance (e.g., Schenk et al., 1986; Smith
et al., 2009) or have no effect on behavioral responses to cocaine (e.g.,
Bozarth et al., 1989; Galaj et al., 2017). However, when EE is employed
as an intervention (i.e., post-cocaine exposure), it appears to be more
consistently effective in moderating cocaine addiction-related beha-
viors. Housing in EE after cocaine exposure can eliminate the expres-
sion of pre-established CPP (Galaj et al., 2017; Solinas et al., 2008),
prevent cocaine-induced reinstatement of preference (Solinas et al.,
2008), and reduce cocaine-induced locomotor activity to cocaine-naïve
levels after behavioral sensitization (Solinas et al., 2008). Also, in ani-
mals well-trained in cocaine self-administration, subsequent housing in
EE reduces responding during extinction training (Chauvet et al., 2009;
Ranaldi et al., 2011) and can reduce or eliminate reinstatement of co-
caine-seeking triggered by the presentation of previously cocaine-
paired conditioned stimuli (Chauvet et al., 2009; Ranaldi et al., 2011;
Thiel et al., 2011, 2009). These results suggest that some feature of EE
may decrease incentive motivation for cocaine and limit the experience
of craving that often precedes relapse.
However, while these studies may effectively demonstrate a re-
duction of cocaine reward and the provocative power of conditioned
stimuli, most animal addiction models may not adequately speak to the
human problems of cocaine abstinence and relapse. The extinction/
reinstatement paradigm is frequently used to model relapse (e.g.,
Chauvet et al., 2009; de Wit and Stewart, 1981; Galaj et al., 2016; Thiel
et al., 2009): drug self-administration behaviors are extinguished by
removing drug reinforcement, and subsequent exposure to the drug or
to conditioned stimuli causes the animal to resume these behaviors. As
noted by Cooper et al. (2007), the human experience of abstinence and
relapse is quite different. Drug-addicted individuals nearly always have
access to their drug of choice, but must endure negative repercussions
(e.g., legal, financial, social) in order to acquire it; the conflicts that
arise from such stressful experiences during drug pursuit can maintain
abstinence (Cooper et al., 2007). In the “conflict model” introduced by
Cooper et al. (2007) animals still have access to the drug, but obtaining
it requires crossing a floor that is electrified by a current that increases
in strength after each day of continued drug-seeking. “Abstinence” is
attained when the animal ceases drug-seeking activity for a predefined
number of IVSA sessions, and “relapse” occurs when drug-seeking re-
sumes upon presentation of an inducing stimulus, such as a drug-paired
cue. Such a design may come closer to emulating the choice a human
addict may face: abstain or endure the consequences of continued use.
Recent studies have demonstrated that this animal conflict model can
be successfully employed in drug addiction research (Barnea-Ygael
et al., 2012; Cooper et al., 2007; Peck et al., 2015, 2013). Previously,
we have shown that EE could accelerate abstinence from heroin seeking
(Peck et al., 2015), but the utility of EE as a therapeutic intervention to
foster cocaine abstinence has not yet been explored.
The present study sought to determine if housing in an enriched
environment may assist in achieving cocaine abstinence within the
animal conflict paradigm when compared to standard housing (non-
EE). Rats well-trained in cocaine self-administration were subsequently
placed in EE or non-EE, and both groups underwent sessions identical to
IVSA training sessions, with the addition of electrified flooring in front
of the self-administration levers. We hypothesized that rats housed in
EE would reach abstinence criteria faster and at a lower electric barrier
strength than non-EE rats. Current strength and latency to achieve ab-
stinence were compared between groups.
36
Pharmacology, Biochemistry and Behavior 166 (2018) 35–41
2. Methods
2.1. Subjects
The subjects were male Long-Evans rats (Charles River, Kingston,
New York, USA; n = 16) weighing 350–380 g at study onset. All rats
were housed individually in standard laboratory cages with free access
to water and food (LabDiet chow). Cages were placed in windowless
rooms with an automated 12-h light/12-h dark cycle, and rats were
only engaged in study procedures during the dark (active) phase of the
cycle. This experiment was conducted in accordance with the National
Institutes of Health guide for the care and use of laboratory animals
(NIH Publications No. 8023, revised 1978) and was approved by the
Queens College Institutional Animal Care and Use Committee.
2.2. Surgery
Each rat was given an intraperitoneal injection of atropine (0.54 mg
in 0.1 mL of distilled water) to reduce salivary and bronchial secretions,
and then anaesthetized with an intraperitoneal injection of sodium
pentobarbital (65 mg/kg). The rat was then placed in a stereotaxic
apparatus, an incision was made on the top of the head, and six screws
were partially implanted into the skull in an oval pattern to mount a
head cap assembly. Next, another incision was made in the neck, the
jugular vein was isolated and opened, and one end of a silastic catheter
(Dow Corning, Midland, Michigan, USA) was inserted into the vein so
that its tip fell just short of the heart. The other end of the catheter was
routed subcutaneously around the neck, emerging from the scalp inci-
sion. Lastly, a head cap assembly was built using a cannula, acrylic
screw, and dental acrylic; the resulting head cap allowed for attachment
to a tether through which cocaine was infused. Both incisions were
stitched, and a topical antibiotic was applied to the neck incision and
around the head cap to prevent infections. To maintain catheter pa-
tency, catheters were flushed with a heparin-saline solution (0.05 mL,
200 U.S.P.) immediately after surgery and after each daily IVSA session.
All animals were housed individually and given 3 days to recover from
surgery before beginning self-administration training.
2.3. Drugs
The cocaine for this experiment was a gift from the National
Institute on Drug Abuse (NIDA), and was delivered in saline solution
(0.125 mL/infusion) at an estimated dose of 1 mg/kg/infusion.
2.4. Equipment
All study sessions were conducted in operant conditioning chambers
run by Med Associates interfacing and software (Georgia, VT).
Chambers measured 26 × 26 × 30 cm and were constructed with 3
aluminum sides, a transparent plastic front, a hinged plastic top, and a
floor of stainless steel rods. Each chamber was housed in a larger,
sound- and light-attenuating wooden box and was illuminated by a
central house light on the inner surface of this box. The back of each
chamber held two levers located 10 cm above the floor; one served as
the active lever and the other as an inactive lever (right and left levers
were designated as active or inactive in a balanced fashion across
chambers). A small white cue light was located 3 cm above each lever.
For IVSA, each rat was attached via head cap assembly to a tethered
line, which was connected to a fluid swivel directly above the chamber.
Polyethylene tubing within the tether provided fluid connection to a
cocaine-filled syringe in a Razel pump (3.33 rpm). The electric barrier
(discussed below) was generated by constant-current aversive stimu-
lators connected to the stainless-steel flooring (Model ENV-414; Med
Associates).
S. Ewing, R. Ranaldi Pharmacology, Biochemistry and Behavior 166 (2018) 35–41

2.5. Procedure 2.5.4. Tail-flick latency assays

2.5.1. Training phase
After recovery from surgery, each rat was randomly assigned to a
single operant conditioning chamber in which to complete all study
sessions. During the training phase, rats underwent daily 3-h sessions
with access to both levers (i.e., the electric barrier was inactive). Presses
on the inactive lever were counted but produced no consequences.
Presses on the active lever were programmed on a fixed ratio one (FR1)
schedule of reinforcement; each press activated the syringe pump to
deliver an infusion of cocaine and illuminated the cue light above the
active lever for 20 s. During this 20 s period, any additional presses on
the active lever were counted but produced no consequences. Presses
on both levers were recorded in 30-min increments.
Daily training sessions were conducted for a minimum of 15 days
(one session per day) and until a stable pattern of cocaine self-admin-
istration was observed. Stable pattern was operationally defined as 5
consecutive sessions in which (1) the number of presses on the active
lever exceeded presses on the inactive lever, (2) intra-session data could
be characterized as having a “loading” period of greater infusions in the
first 30 min, followed by a “maintenance” period of reduced but con-
sistent infusions for the rest of the session and (3) the total number of
infusions for each session was within ± 10% of the average total
number of infusions for these 5 sessions. During this phase, all rats were
returned to individual, standard laboratory housing between sessions.
Tail-flick latency assays were conducted 24 h after the last training
phase session but before assignment to housing conditions and then
again after completion of the EBA phase. For each assay in each rat, a
concentrated beam of radiant heat was focused 1–2 cm from the end of
the tail, and tail-flick reaction times were recorded. Heat intensity was
programmed to elicit an average reaction time of 2–4 s and to auto-
matically shut off after 10 s to prevent tissue damage. Three trials were
conducted at each time point and the average was calculated for ana-
lysis.
2.6. Data analysis
A 3-way mixed factorial analysis of variance (ANOVA;
Day × Lever × Condition) was conducted to analyze lever-pressing for
both groups in the 5 final training sessions, prior to assignment to ex-
perimental housing conditions. A 2-way mixed factorial ANOVA
(Lever × Condition) analyzed lever-pressing on Day 1 of the EBA phase.
Mean tail-flick latency values were compared between groups at both
time points (pre- and post-EBA phase) simultaneously with a 2-way
mixed factorial ANOVA (Condition × Time). A one-tailed, independent
samples t-test was used to evaluate our directional hypothesis regarding
final current strengths at completion of the EBA phase. Due to a nor-
mality violation, the number of days spent in the EBA phase was com-
pared between conditions using a one-tailed Mann-Whitney U test.

2.5.2. Housing assignment
After completing the training phase, rats were randomly assigned to
one of two experimental conditions. Rats assigned to environmental
enrichment (EE; n = 8) were placed individually in 36 × 66 × 41 cm
clear plastic cages equipped with a running wheel, a PVC tunnel, and a
selection of toys including jingle balls, chew toys, and stuffed animals.
Toys were rotated daily to provide a variety of interactive stimuli. Rats
assigned to standard housing (non-EE; n = 8) were placed individually
in fresh standard housing cages identical to the housing described
above. Each rat was placed in its respective housing the day after its last
training session and given an additional 24 h of rest before beginning
the next phase. Rats returned to these housing conditions after each
session for the remainder of the study.
3. Results
3.1. Training phase
Prior to assignment to housing conditions, all rats pressed more on
the active lever than on the inactive lever during the last 5 sessions of
IVSA training. Furthermore, lever pressing levels were similar for both
groups across all 5 days (Fig. 1) and within each session (data not
shown). A 3-way ANOVA (Lever × Condition × Session) found a sig-
nificant main effect of Lever, F(1,14) = 212.558, p < 0.001, but no
group differences were observed.
3.2. Electric barrier/abstinence (EBA) phase
On the first day of the EBA phase, all rats continued to press more on

2.5.3. Electric barrier/abstinence phase (EBA)

During the EBA phase, each rat was placed in its assigned operant
conditioning chamber for daily 35-min sessions. Conditions within the
chamber were identical to those in the training phase, with two excep-
tions. First, active lever presses were programmed on a fixed ratio two
(FR2) schedule of reinforcement. Second, this phase introduced an
electric barrier in front of the levers; the two-thirds of flooring adjacent
to the levers was electrified, and the third of flooring furthest from the
levers provided a non-electrified “safe zone”. In order to reach the ac-
tive lever to receive a cocaine infusion, the rat needed to leave this “safe
zone” and subject itself to foot shocks.
On the first session of the EBA phase, an electric current strength of
0.25 mA was used for all rats. Before each session rats were placed in
the “safe zone,” and for the first 5 min of the session the levers were
retracted. After 5 min the levers were inserted, permitting cocaine self-
administration for the remaining 30 min. If a rat pressed on the active
lever during the session, the subsequent session's current strength was
increased by 0.04 mA. If a rat did not press on the active lever, the same
current strength was used during the subsequent session. This proce-
dure continued until the rat did not press on the active lever for 3
consecutive sessions (i.e., achieved abstinence) or the rat continued Fig. 1. Mean ( ± SEM) presses on the active and inactive levers during the last five
drug-seeking for 5 consecutive sessions at the maximum current training phase sessions, prior to random assignment to housing conditions. Active lever
strength (1.0 mA). The number of days spent in the EBA phase and presses exceeded inactive lever presses (p < 0.001) but no condition differences were
observed.
electric current strength at completion were recorded for analysis.

37
S. Ewing, R. Ranaldi
Fig. 2. Mean ( ± SEM) presses on the active and inactive levers during the first session of
the electric barrier/abstinence phase, after assignment to EE or non-EE. Active lever
presses exceeded inactive lever presses (p < 0.001) but no condition differences were
observed.
Fig. 3. Current strength (mA) at which each rat completed the electric barrier/abstinence
phase, and the condition means ( ± SEM). *The difference in condition means was found
to be significant, p < 0.05, one-tailed.
Fig. 4. Number of days that each rat spent in the electric barrier/abstinence phase, and
the condition means ( ± SEM). *In a Mann-Whitney U test, the difference in condition
medians was found to be significant, p < 0.05, one-tailed.
38
Pharmacology, Biochemistry and Behavior 166 (2018) 35–41
Fig. 5. Mean ( ± SEM) tail-flick latency for each condition before and after the electric
barrier/abstinence phase. No significant differences were observed.
the active lever than the inactive lever, and EE rats did not differ from
non-EE rats in lever-pressing levels (Fig. 2). However, EE rats ceased
pressing on the active lever at lower currents (Fig. 3) and after fewer
days (Fig. 4) than non-EE rats. A 2-way ANOVA on the data from the
first day of the EBA phase showed only a main effect of Lever, F
(1,14) = 21.206, p < 0.001. The non-EE rats reached abstinence cri-
teria after a significantly greater number of sessions (median = 18)
than EE rats (median = 10), Mann-Whitney U = 1.5, p = 0.014, one-
tailed, and at significantly higher current levels, t(14) = 2.02,
p = 0.031, one-tailed.
3.3. Tail-flick assays
Post-EBA phase tail-flick assays could not be obtained for 2 of the 16
animals, one from each condition: these rats were found to be ill on the
day of their scheduled assay and it was determined that the data would
not be valid. Tail-flick latencies were similar before and after the EBA
phase for all rats, and no differences were found between housing
conditions at either time period (Fig. 5). A 2-way ANOVA found no
significant main effects or interactions.
4. Discussion
In animals well-trained in cocaine IVSA, rats that were subsequently
housed in enriched environments attained abstinence from cocaine
seeking after fewer sessions and at lower current strengths than non-EE
rats after the introduction of an electrified barrier in front of the self-
administration levers. These results suggest that abstinence from ad-
diction-related behaviors, as measured by sustained cessation of co-
caine self-administration, can be facilitated by exposure to environ-
mental enrichment.
While it may be possible that housing in EE reduced cocaine-seeking
by intensifying the aversive experience of the electric shocks, the
comparative results of pre/post-tail-flick assays do not support a dif-
ference in nociception (as measured by reflexive reactions to painful
stimuli) between EE and non-EE rats. Previous research comparing
heat-induced reactivity to that of electric foot-shock have found the two
to be functionally similar measures of analgesia in rodents (Bodnar
et al., 1981; Kepler et al., 1991; Kiefel and Bodnar, 1992), and thermal
pain thresholds in each group were shown to be similar before and after
the EBA phase (thus, were not affected by EE).
This work is in line with previous self-administration studies, which
S. Ewing, R. Ranaldi
also found access to EE to be an effective intervention for cocaine
seeking. For example, Chauvet et al. (2009) found that when access to
cocaine reinforcement is removed after self-administration training,
30 days of EE housing significantly reduced responding during a 6-h
extinction session when compared to non-EE. Another group reported
that 21 days in EE with social features (5 rats per cage) facilitated ex-
tinction and attenuated cue-induced reinstatement of cocaine seeking
when compared to non-EE and paired-housing conditions (PC, 2 rats
per standard cage; Thiel et al., 2009) and 17 days of EE with concurrent
extinction training sessions accelerated extinction of cocaine seeking
and attenuated reinstatement significantly more than daily handling or
extinction training in non-EE (Thiel et al., 2011). Our lab has previously
shown that 10 days of EE exposure can reduce cocaine seeking in un-
familiar environmental contexts and can attenuate context-renewal-
elicited reinstatement of cocaine seeking (Ranaldi et al., 2011). Also,
we have demonstrated that EE can facilitate heroin abstinence within
the animal conflict model when introduced one day before the EBA
phase (Peck et al., 2015), as in the present study. Unlike extinction/
reinstatement experiments, these latter results (Peck et al., 2015) paired
with the results of the present study may suggest a utility of EE ex-
posure for promoting abstinence from drugs of abuse; in these animals,
activity ceases in the presence of aversive consequences to drug-seeking
and despite the continued availability of drug reinforcement (Cooper
et al., 2007). Variability is likely with regards to substance-specific
response to enrichment [for example, Peck et al., 2015 found a decrease
in responding for heroin after only one day of EE exposure, unlike in the
present study], but these results suggest that promoting abstinence with
EE interventions may be worth exploring with a variety of drugs of
abuse.
Decades of research into the effects of post-natal environmental
enrichment, EE rearing and/or long-term exposure to EE have found a
wide variety of neurological benefits (for a review, see Simpson and
Kelly, 2011): neurochemical transmission is affected in ways that pro-
mote neuroplasticity, enhance neuronal communication, and decrease
activity associated with depression and anxiety (Darna et al., 2015;
Solinas et al., 2010; van Praag et al., 2000); while extracellular dopa-
mine levels appear to be unaffected, EE can reduce expression of do-
pamine receptors as well as the expression and activity of dopamine
transporters (DAT), the primary target of cocaine within the brain (Del
Arco et al., 2007; Neugebauer et al., 2004; Zhu et al., 2005, 2004);
neurotrophic factors are increased in various areas of the brain, en-
hancing efficiency of neuronal networks (Ernfors et al., 1990; Ickes
et al., 2000; Korte et al., 1998; Martinowich and Lu, 2008; Torasdotter
et al., 1998); and brain size/weight, neurogenesis, synaptogenesis,
cortical thickness, and spine density are enhanced with EE (Bennett
et al., 1969; Johansson and Belichenko, 2002; Leggio et al., 2005; van
Praag et al., 2000). That DAT activity and expression is reduced in the
medial prefrontal cortex after EE exposure (Neugebauer et al., 2004;
Zhu et al., 2005, 2004) has been implicated in enhancement of in-
hibitory control in animal models of impulsive choice (e.g., Perry et al.,
2008; Stairs and Bardo, 2009; Wood et al., 2006), which plays a crucial
role in substance abuse vulnerability (for a review, see Perry and
Carroll, 2008). However, it may be important to note that the reduction
in cocaine-seeking observed here occurred after relatively brief ex-
posure to EE. After completion of the training phase, animals were given
only 24 h in their new habitats before commencing with EBA sessions,
and EBA sessions typically occurred on consecutive days. Therefore, the
fact that EE rats achieved 3 consecutive days of abstinence after a
median of 10 sessions (compared to a median of 18 sessions for non-EE
rats) indicates that some of the abstinence-promoting neurochemical
and/or neuroplastic effects of EE exposure may begin after less than one
week, but it is unlikely that these animals have experienced the same
degree of change as those that developed in or spent extended amounts
of time (> 60 days) in enriched conditions.
At present, there is limited evidence available within the literature
of gross neuroanatomical changes resulting from short-term
39
Pharmacology, Biochemistry and Behavior 166 (2018) 35–41
(< 30 days) EE exposure that may explain the behavioral observations
of the present study. However, recent research examining c-fos ex-
pression has shown that animals placed in EE for as few as 30 days after
drug exposure may experience significantly lower activation in the
mesocorticolimbic system in response to drug-paired stimuli. Rats
trained in cocaine self-administration that were placed in larger cages
with novel objects and conspecifics showed lower levels of c-fos after
response-contingent conditioned cues (light and noise) in the prelimbic
cortex, basolateral (BL) amygdala, and the orbitofrontal cortex (OFC)
than rats housed in impoverished conditions (IC, similar to non-EE in
the present study; Thiel et al., 2010). Moreover, EE rats had sig-
nificantly less c-fos in the infralimbic and anterior cingulate cortices
(ACC), the nucleus accumbens (NAc), the bed nucleus of the stria ter-
minalis (BNST), and the ventral tegmental area (VTA) than IC and PC
rats (Thiel et al., 2010). Similarly, Chauvet et al. (2011) found that mice
housed in EE showed less c-fos expression than non-EE mice (similar to
saline-conditioned controls) in the ACC, lateral caudate putamen, NAc
shell, dentate gyrus of hippocampus, BL and central amygdala, BNST,
and VTA when placed in drug-paired compartments 30 days after es-
tablishing cocaine-conditioned place preference (Chauvet et al., 2011).
As these structures have been implicated in drug-seeking behaviors
(Bossert et al., 2005; Feltenstein and See, 2008; Kalivas, 2008; Koob
and Le Moal, 2001; Shalev et al., 2002; Vanderschuren et al., 2005), it is
possible that the EE-specific reduction of activity in these areas is also
reducing cue-elicited incentive motivation for cocaine, and behavioral
observations from these studies support this notion (Chauvet et al.,
2011; Thiel et al., 2010). Though the present study cannot adequately
address this hypothesis without comparative c-fos data, if a correlation
does exist, our behavioral data suggest that this reduction in meso-
corticolimbic activation may initiate in fewer than 7 days of EE ex-
posure.
One dominant theory as to the apparent protective utility of EE
stipulates an EE-induced reduction in stress. In humans and animals
alike, an increase in stress often leads to an increase in addiction-related
behaviors, while lower levels and a lesser degree of HPA axis activation
in response to stressful stimuli often correlate with a reduction in these
behaviors. Previous studies looking at basal corticosterone levels after
EE exposure have yielded inconsistent results (see Simpson and Kelly,
2011), but HPA reactivity (as measured by adrenocorticotropic hor-
mone release after acute stressors) has been found to be significantly
reduced in EE rats (Moncek et al., 2004; Morley-Fletcher et al., 2003;
Schrijver et al., 2002). In drug self-administration studies, this reduc-
tion is correlated with a reduction in drug-seeking behaviors (Deroche
et al., 1997, 1997; Deroche-Gamonet et al., 2003; Goeders and Guerin,
1994, 1996; Stairs and Bardo, 2009). Although compelling, within the
present study this hypothesis cannot be objectively evaluated; though
accelerated abstinence in rats may be indicative of reduced stress, some
studies have shown that thigmotactic behaviors (wall-hugging) and
lower levels of exploratory behaviors (freezing) may actually indicate
higher levels of stress (Pena et al., 2009; Simpson and Kelly, 2011). As
abstinent animals remained mostly stationary in the “safe zone”, it is
difficult to assert that this theory best explains these behavioral data
without chemical assays. However, the studies described previously
lend considerable weight to this idea.
Crofton et al. (2015) have proposed an “inoculation stress theory”
regarding the effects of EE on stress reactivity. According to these au-
thors, rather than providing an alleviation of stress, enriched conditions
subject animals to constant, low levels of predictable and manageable
stressors (Crofton et al., 2015). In contrast to effects induced by acute
stressors typically employed by investigators (e.g., forced-swim, con-
straint, saline injections), the stress induced by rotation of novel sen-
sory stimuli may increase efficiency of HPA signaling, ultimately re-
ducing activation by acute stressors (Crofton et al., 2015) such as
context-elicited cocaine cravings or the electric barrier used in this
study. Foot-shock stress has previously been shown to increase drug-
seeking (e.g., delayed extinction, reliable stress-induced reinstatement)
S. Ewing, R. Ranaldi
when administered in the IVSA environment (Highfield et al., 2000; for
a review, see Shaham et al., 2000) and human cocaine abusers report an
increase in cocaine cravings after stress induction in experimental set-
tings (Sinha et al., 1999). The inoculation stress theory would propose
that foot-shock stress is reduced in environmentally-enriched rats;
while it may be argued that this would encourage the animal to cross
the barrier, a reduction in stress-induced cocaine cravings may reduce
incentive motivation to do so. Thus, by this reasoning, it would seem
that under the current conditions the putative capacity of EE to reduce
barrier-induced stress and encourage barrier-crossing is overcome by its
putative capacity to reduce stress-induced craving and by extension the
motivation to cross the barrier, resulting in less drug seeking. Future
studies might evaluate the effect of the electric barrier on adreno-
corticotropic activity and its relationship with environmental enrich-
ment, cocaine seeking, and drug abstinence.
Other limitations to this study include homogeneity of animal
subjects (all rats were of the same breed and gender and were of similar
age and weight at study onset) and the absence of a cocaine dose-re-
sponse analysis. It may be important to explore these factors within the
animal conflict model.
Evidence that environmental enrichment leads to a variety of neu-
rological, cognitive, and behavioral benefits continues to accumulate.
Drug research has demonstrated that EE exposure can significantly re-
duce addiction-related behaviors in animals, and the present study may
suggest a utility of EE in promoting abstinence from cocaine-seeking.
While many theories exist to explain this phenomenon, the exact neu-
rological mechanisms involved remain to be discovered. Further ex-
ploration of enrichment features and their relationship with drug-re-
lated behaviors may lead to improved interventions for drug addiction.
Conflicts of interest
None.
Acknowledgments
Special thanks to Ewa Galaj and Monica Manuszak for their assis-
tance with this experiment.
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