Competition Between Novelty and Cocaine Conditioned Reward Is Sensitive to Drug Dose and Retention Interval

Behavioral Neuroscience
© 2010 American Psychological Association
2010, Vol. 124, No. 1, 141–151
0735-7044/10/$12.00
DOI: 10.1037/a0018226
Competition Between Novelty and Cocaine Conditioned Reward Is
Sensitive to Drug Dose and Retention Interval
Carmela M. Reichel and Rick A. Bevins
University of Nebraska–Lincoln
The conditioned rewarding effects of novelty compete with those of cocaine for control over choice
behavior using a place conditioning task. The purpose of the present study was to use multiple doses of
cocaine to determine the extent of this competition and to determine whether novelty’s impact on cocaine
reward was maintained over an abstinence period. In Experiment 1, rats were conditioned with cocaine (7.5,
20, or 30 mg/kg ip) to prefer one side of an unbiased place conditioning apparatus relative to the other.
In a subsequent phase, all rats received alternating daily confinements to the previously cocaine paired
and unpaired sides of the apparatus. During this phase, half the rats had access to a novel object on their
initially unpaired side; the remaining rats did not receive objects. The ability of novelty to compete with
cocaine in a drug free and cocaine challenge test was sensitive to cocaine dose. In Experiment 2, a place
preference was established with 10 mg/kg cocaine and testing occurred after 1, 14, or 28 day retention
intervals. Findings indicate that choice behaviors mediated by cocaine conditioning are reduced with the
passing of time. Taken together, competition between cocaine and novelty conditioned rewards are
sensitive to drug dose and retention interval.
Keywords: reward competition, Pavlovian conditioning, sensation seeking, exploratory behavior, con-
ditioned place preference
In the case of drug abuse, one aspect of addiction may involve
and nondrug rewarding stimuli, including cocaine versus pups
the excessive choice of a drug over other aspects of the addict’s
(Mattson, Willams, Rosenblatt, & Morrell, 2001), cocaine versus
life (Winger, Woods, Galuska, & Wade-Galuska, 2005). Thus,
social interaction (Thiel, Okun, Neisewander, 2008), and cocaine
intervention strategies may benefit by understanding the influence
versus novel objects (Reichel & Bevins, 2008).
of associative learning on choice behavior. From a conditioning
The interaction between conditioned cocaine reward and nov-
perspective, learning histories that include drug-associated stimuli
elty seeking is particularly interesting given that individuals that
may influence choice behavior during treatment or abstinence. The
seek highly rewarding stimuli are more vulnerable to drug abuse
place conditioning procedure allows one to study the learning
(Zuckerman & Kuhlman, 2000). This correlation between drug use
processes involved in associatively motivated choice behavior
and the sensory/novelty-seeking characteristic has been attributed
(Bardo & Bevins, 2000). One way to compare the impact of
to an overlap in the rewarding properties of abused drugs and
conditioned associations on choice behavior is with a variation of
response to novel situations (Bardo, Donohew, & Harrington,
the traditional place conditioning procedure. Rather than compar-
1996; Bardo & Dwoskin, 2004; Bevins, 2001). Preclinical animal
ing a drug to saline, as is typically done, a known rewarding
research has shown that presentation of novel stimuli or placement
stimulus (e.g., cocaine) can be compared to some other value of the
in a novel environment can decrease drug intake (Cain, Smith, &
same stimuli or to a different stimulus (i.e., another cocaine dose
Bardo, 2004; Thompson & Ostlund, 1965). In a place conditioning
or different drug; Barr, Paredes, & Bridger, 1985; Bevins, 2005;
procedure, presentation of a novel object can potentiate the re-
Groblewski, Bax, & Cunningham, 2008; Patkina & Zvartau,
warding effects of a low dose of cocaine (Bevins, 2001). More so,
1998). Recently, several laboratories also have studied associa-
our laboratory recently demonstrated that the conditioned reward-
tively motivated choice behaviors with comparisons between drug
ing effects of novelty can alter choice involving drug reward
(Reichel & Bevins, 2008).
In these studies, rats were initially conditioned with cocaine (7.5
Carmela M. Reichel and Rick A. Bevins, Department of Psychology,
mg/kg ip) to prefer one side of an unbiased place conditioning
University of Nebraska–Lincoln.
apparatus. In the subsequent phase, all rats received alternating
This research was supported by a NIH National Research Service Award
daily confinements (10 min) to the previously cocaine-paired and
(DA023283) and an American Psychological Association Dissertation Re-
unpaired (i.e., saline) sides of the apparatus. Consequently, when
search Award to Carmela M. Reichel. Additional support for the research
rats were placed on the previously cocaine-paired side, they were
was provided by DA017086 and DA018114. We thank Jessica Barr, Erin
subjected to procedural extinction. That is, rats experienced the
Ryan, and Andrea Wilson for their assistance scoring the videotapes and
drug paired environment (conditioned stimulus [CS]) without the
conducting reliability checks.
physiological effects of the drug (unconditioned stimulus [US];
Correspondence concerning this article should be addressed to Carmela
Pavlov, 1927; Rescorla, 2004). During this phase, half the rats had
M. Reichel, Department of Neuroscience, Medical University of South
Carolina, 173 Ashley Avenue, MSC 510, Charleston SC 29425. E-mail:
access to a novel object on their initially unpaired side (i.e.,
reichel@musc.edu
novelty rats), whereas the other half did not have objects (i.e.,
141

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REICHEL AND BEVINS
control rats). Rats were tested in a drug free and cocaine state. On
removable pieces of metal to form a placement area (6.5
15.5
the drug free test, the cocaine-conditioned preference was elimi-
19.5 cm). During conditioning, a solid aluminum floor the same
nated for the novelty rats, but not for control rats. This pattern of
length as that used in the center compartment (6.5 cm) was placed
choice behavior persisted even in the cocaine state. Thus, pairing
in each end chamber nearest the wall blocking access to the center
the previously unpaired environment with novel objects shifted a
compartment. This maneuver reduced the novelty of this floor on
preference away from the cocaine-paired environment during drug
postconditioning choice tests. The novel objects used were a white
free and drug challenge tests.
sock (about 40-cm long), a white PVC pipe (8-cm long; 10.5-cm
The competition previously described was only characterized
diameter), a plastic scouring pad (9-cm diameter) attached to a
with one cocaine dose at one retention interval. The extent of this
paint roller (7.5-cm long, 4-cm diameter), and a sheet of newspa-
competition is unknown. It is possible that higher doses of cocaine
per wadded into a ball (cf. Bevins et al., 2002; Reichel & Bevins,
may be more resistant to competition by novelty or that competi-
2008).
tion will not exist after longer retention intervals. Therefore, the
purpose of this current study was twofold. First, in Experiment 1,
Drugs
we characterized the relation between conditioned novelty and
cocaine reward by assessing competition across a range of cocaine
Cocaine hydrochloride was purchased from Sigma Chemicals
doses (i.e., 7.5, 20, or 30 mg/kg). This range of doses was chosen
(St. Louis, MO), dissolved in saline (0.9% NaCl) and injected
based on preliminary data from our laboratory showing reliable
intraperitoneally at a volume of 1 ml/kg.
cocaine place condition with these doses. Recent clinical studies in
human cocaine users report consumption ranges from 0.54 to 12g
Statistical Analysis
per week (Colzato, van den Wildenberg, & Hommel, 2008;
Garcia-Rodriguez et al., 2009; Pace-Schott et al., 2008). Using an
Dependent measures.
The main dependent measure during
average body weight of 70 kg this range converts to 7.7 to 171.42
habituation and all ensuing test sessions was time spent (in sec-
mg/kg/week. In regards to our cocaine doses, rats received 30
onds) in each compartment. Sessions were videotaped and ob-
mg/kg (4 injections of 7.5 mg/kg) to 120 mg/kg (4 injections of
served later. Criterion for a rat to be considered in a compartment
30 mg/kg) over 8 days. Keeping in mind species differences and
required the forelegs, head, and shoulders to be positioned inside
administration routes, our dose range can be considered low to
the compartment. A secondary measure was horizontal activity
moderate in relation to human consumption. Second, in Experi-
(defined as the number of times the rat’s front paws crossed a
ment 2, we determined whether novelty’s ability to compete with
center line that bisected the end compartments) in each end com-
cocaine persisted or if the initial drug preference returned after a
partment. The total number of line crosses during the session
period of abstinence. Previously, we reported that novelty reward
defined activity. Observers’ na?¨ve to the experimental conditions
can compete with cocaine reward when tested 24 to 48 hr later
conducted interobserver reliability checks on both measures. A
(drug free and drug challenge tests, respectively; Reichel & Bev-
total of 34 time and activity observations in common were ana-
ins, 2008). This question is of particular interest because long-term
lyzed with Pearson’s product-moment correlation analysis (rs
intervention strategies are essential to alleviate the relapse of
.90, ps
.001).
drug-seeking behaviors.
Data analysis.
On the habituation day, paired t tests were used
to analyze the time spent and activity counts in each end compart-
ment (i.e., rods vs. holes) to demonstrate the unbiased construction
General Method
of our apparatus. For all other test days, two- or three-way analysis
of variance (ANOVA) was used to analyze time spent in each end
Subjects
compartment and activity counts. Type I error rate was controlled
Experimentally na?¨ve male Sprague–Dawley rats (N
143)
for by Tukey’s honestly significant difference (HSD) post hoc
were 250 to 300 g at the time of delivery. They were individually
comparisons. Statistical significance was declared at p
.05 for
housed in a temperature and humidity controlled colony on a 12-hr
all tests and only significant values are reported.
light– dark cycle in plastic cages 48.3
24.1
21.0 cm (l
w
h) with stainless steel lids. Water and food were available contin-
Experiment 1
uously in the home cage. The experimental protocols followed the
“Guide for the Care and Use of Laboratory Animals” (National
The Extent That Novelty Conditioned Reward
Research Council, 1996) and were approved by the University of
Competes With Cocaine Conditioned Reward
Nebraska–Lincoln Institutional Animal Care and Use Committee.
Habituation.
To confirm the unbiased construction of the
Apparatus
apparatus and provide experience with the later testing procedure,
rats were set onto the center placement area and allowed free
Experiments were conducted in two identical aluminum and
access to explore both end compartments for 10 min. Conditioning
Plexiglas chambers having two distinct compartments (each com-
groups were then assigned in an unbiased fashion (cf. Bevins &
partment
40
16
20 cm) separated by a smaller area for
Cunningham, 2006).
placement. Different floor types created distinct end compart-
Cocaine place conditioning.
These procedures were previ-
ments. One floor had approximately 340 1.3-cm holes drilled into
ously described in Reichel and Bevins (2008). All placements into
a 16-gauge aluminum sheet. The other floor had 1-cm rods made
the compartments were counterbalanced according to rods/holes,
from stainless steel. The center placement area was created by
spatial orientation, and whether drug pairing occurred on the first

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COCAINE CONDITIONED REWARD SENSITIVITY
143
or second day of conditioning (Bevins & Cunningham, 2006). On
only the novelty group experienced the novel objects on the
the first conditioning day, half the rats were injected with cocaine
previously saline-paired side.
(7.5, 20, or 30 mg/kg ip) immediately before placement into their
Drug free and drug challenge test days.
The drug free test
paired compartment. The other half were administered saline be-
was conducted 24 hr after completion of the competing condition-
fore placement into the unpaired compartment. On the second day
ing phase. On the drug free test day, rats were given saline, placed
of conditioning, rats that were injected with cocaine on the previ-
in the center compartment, and allowed to explore both sides of the
ous day received saline; rats that received saline were injected with
apparatus for 10 min. On the drug challenge test day (24 hr after
cocaine and placed in the opposite compartment. Alternating daily
the drug free test), rats were injected with their conditioning dose
placements lasted for 8 consecutive days and were separated by 24
of cocaine before placement in the center compartment and al-
hr. On the test day, rats were placed into the center placement area
lowed free access to the entire apparatus for 10 min. Because our
after an injection of saline and allowed to roam the apparatus for
primary interest was the choice behaviors in a drug free state, this
10 min.
test preceded the drug challenge test for all rats.
Competing conditioning.
The competing conditioning phase
occurred 24 hr after the last conditioning session (see Figure 1, for
a schematic representation). Rats were assigned to control or
Results
novelty groups with a restriction that the groups did not differ on
the initial place conditioning score. Alternating daily placements
Habituation.
Prior to cocaine conditioning, rats did not ex-
were preceded by saline injections and lasted for 10 min. When
hibit a bias toward one particular stimulus (holes vs. rods) over the
rats were restricted to their previously cocaine-paired compart-
other. The mean (
SEM) time spent in the holes versus rods
ment, they experienced the drug associated cues in the absence of
compartment was 268.4 (
3.89) and 260.4 (
3.73), respectively.
the drug effect (i.e., extinction). This type of procedural extinction
Activity on the holes side was 32.3 (
.81) and on rods was 33.2
refers to re-exposure to the CS (i.e., exteroceptive cues of the
(
.77).
paired environment) without the US (Pavlov, 1927; Rescorla,
Place conditioning.
Figure 2 shows the seconds spent in each
2004). The rats in these experiments were placed on extinction of
compartment on the 3 test days for control (left panel) and novelty
the cocaine-associated cues of the paired environment when they
(right panel) rats. For control rats (n
12), conditioning with 7.5
were confined to this environment during the novelty-conditioning
mg/kg cocaine (Figure 2A, upper left graph) resulted in more time
phase and did not receive drug. When rats were placed on the
previously saline-paired side, rats in the novelty group had access
spent in the cocaine-paired compartment on all 3 test days. This
to a different novel object on each placement. Control rats did not
observation was supported by a main effect of side, F(1, 11)
have access to objects. More important, both groups received
25.66, p
.001. Novelty rats (n
11, Figure 2A, upper right
procedural extinction on the previously cocaine-paired side, but
graph) conditioned with 7.5 mg/kg cocaine, only preferred the
cocaine-paired side on the initial test of cocaine place condition-
ing, Side
Test interaction, F(2, 20)
4.72, p
.021 and
Tukey’s post hoc, p
.05.
Figure 2B shows the time spent in each end compartment for
rats conditioned with 20 mg/kg cocaine. Control rats (n
12,
center left graph) also preferred the cocaine-paired side on all 3
test days, main effect of side, F(1, 11)
22.14, p
.001. For
novelty rats (n
12, center right graph) conditioned with 20
mg/kg cocaine compartment preference varied over test days as
indicated by a Side
Test interaction, F(2, 22)
9.99, p
.001.
This group preferred the drug paired side on the initial test of
cocaine place conditioning and on the drug challenge test day
(Tukey, p
.05). The main effects of side, F(1, 11)
17.23, p
.002, and test, F(2, 22)
6.29, p
.007, were also significant.
Figure 2C shows the data for rats conditioned with 30 mg/kg
cocaine. Both groups, control (n
12, lower left graph) and
novelty (n
12, lower right graph) preferred the drug paired side
on all 3 test days, main effects of side: control, F(1, 11)
31.19,
p
.001, novelty, F(1, 11)
30.38, p
.001.
Activity.
Figure 3 shows the activity data for the novelty and
control groups conditioned with the three different cocaine doses.
The two-way interaction of Cocaine
Test was significant, F(4,
Figure 1.
Compartment placements throughout the experimental phases
130)
3.24, p
.014, as were the main effects of test, F(2,
are represented with this schematic representation. Rats were conditioned
130)
7.90, p
.004, and cocaine, F(2, 65)
5.45, p
.006.
and assigned to groups in an unbiased fashion. All compartment place-
Post hoc Tukey’s test show that drug challenges with 20 and 30
ments were counterbalanced according to rods/holes, spatial orientation,
mg/kg cocaine increased activity in comparison to the initial test of
and whether drug and novelty pairings occurred on the first or second day
of conditioning.
place conditioning and the drug free test ( p
.05).

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REICHEL AND BEVINS
Figure 2.
Mean time (
SEM) spent in seconds for rats in the control and novelty groups conditioned with 7.5,
20, and 30 mg/kg cocaine on the three tests of place conditioning in Experiment 1. Panel A shows data for rats
conditioned with 7.5 mg/kg cocaine. Panel B represents data from the 20 mg/kg conditioning group and Panel
C from the 30 mg/kg group. The control group is represented in the left column and the novelty group on the
right. PC
place conditioning; DF
drug free; DC
drug challenge. Indicates significant difference between
compartments.
Discussion
fact, control and novelty rats conditioned with 30 mg/kg cocaine
preferred the cocaine-paired side whether tested in a drug or drug
The ability of novelty to compete with cocaine in a drug free and
free state and both groups conditioned with 20 mg/kg cocaine
cocaine-challenge test was sensitive to cocaine dose and drug state.
preferred the cocaine-paired side on the drug challenge test. How-
More important, this experiment identified the limitations of nov-
ever, the conditioned rewarding effects of novelty competed
elty competition because preferences formed with higher doses of
against the previously established 7.5 and 20 mg/kg cocaine-
cocaine were more resistant to competition by novelty reward. In
conditioned preference in the drug free state. This competition

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COCAINE CONDITIONED REWARD SENSITIVITY
145
Figure 3.
Mean activity counts ( SEM) for rats conditioned with 7.5, 20, or 30 mg/kg cocaine in the control
and novelty groups for Experiment 1. PC
place conditioning; DF
drug free; DC
drug challenge.
Indicates significant difference on the drug challenge test in comparison to both other tests for rats in both
groups.
remained even in the cocaine state for 7.5 mg/kg cocaine. Lower
Bevins, 2008). One account of this finding is that novelty and
doses of cocaine were more sensitive to novelty competition. This
cocaine reward are indistinguishable and generalized to each
outcome is consistent with a study by Cain and colleagues (2004)
one another on test day for the novelty group. However, the
using amphetamine self-administration in rats. In that experiment,
dissociation between cocaine doses discounts such an account.
they found that the opportunity to interact with a novel object
In Phase 1 of our experiment, cocaine enters into a conditioned
during self-administration of low (0.003 and 0.01 mg/kg/infusion)
association with the environment and saline does not. Thus, the
amphetamine doses reduced the number of drug infusions, but the
choice was between an environment paired with cocaine versus
novel object had no impact on responding at higher doses (0.03
an environment that has been equally exposed with saline
and 0.056 mg/kg/infusion).
injections. Such a comparison results in more time spent in the
The differences in compartment choice in the present study were
cocaine-paired environment on tests. During the novelty-
not attributable to cocaine’s locomotor activating effects because
conditioning phase, another stimulus with conditioned reward-
on all 3 test days the groups never differed on activity measures.
ing value (i.e., novel objects) is presented so that all ensuing
This comparison is methodologically important because of con-
tests are relying on a comparison between conditioned rewards
cerns about the influence of motor activity on the expression of a
(see Bevins, 2005; Bardo & Bevins, 2000, for theoretical ac-
compartment preference, particularly when drug is on board during
counts of the learning that occurs in place conditioning).
testing. Indeed, on drug challenge tests 20 and 30 mg/kg cocaine
Changing the nature of the tests prompts the possibility that the
increased activity counts relative to the drug free tests. Despite this
conditioned rewarding effects of cocaine and those of novelty
increase, compartment preferences were expressed for both control
generalized to both compartments on test day. That compart-
and novelty groups with these doses of cocaine. This pattern
ment preferences were dissociated between the 7.5 and 20
dispels any concern about changes in sensory-motor processing
mg/kg cocaine treated novelty groups demonstrates that rats
having interfered with a subject’s ability to approach and maintain
were able to distinguish between environments even though
contact with the stimulus in the present experiment (Gremel &
both environments were associated with an appetitive stimulus,
Cunningham, 2007).
diminishing the likelihood that stimulus generalization was
The finding that competition involving the conditioned reward-
responsible for the choice competition exhibited in this exper-
ing effects of novelty was sensitive to cocaine dose is notable
iment. In other words, the conditioned association between the
given that a place conditioning task is typically insensitive to dose
environment (i.e., end compartment) and the reward contained
effects. Indeed, one limitation of the place conditioning procedure
specific information about the nature of the reward (novelty vs.
is that conditioned choice is often “all-or-none” (e.g., Bardo &
Bevins, 2000). That is, once the dose of drug of interest has
7.5, 20, or 30 mg/kg cocaine). Such a conclusion is consistent
crossed some threshold for reward (i.e., conditions a place prefer-
with a growing body of research on Pavlovian conditioning
ence), higher doses do not typically generate greater preferences
processes involving nondrug USs (cf. Corbit & Balleine, 2005;
for the paired environment (Bardo & Bevins, 2000; Bardo,
Delamater & Holland, 2008; Konorski, 1967).
Rowlett, & Harris, 1995; Bevins, 2005; Mueller & Stewart, 2000;
In sum, this experiment demonstrated that the introduction of an
O’Dell, Khroyan, & Neisewander, 1996). Presumably, this all-or-
alternative reward during extinction training (i.e., during the sec-
none pattern reflects the unchanging comparison between condi-
ond experimental phase) can shift compartment preferences de-
tioned drug reward (paired) and similar familiarization and injec-
pending on cocaine dose (7.5, 20, or 30 mg/kg) and its presence in
tion number as the paired environment without the reward
the central nervous system (drug free vs. drug challenge tests).
(unpaired). By changing the nature of the comparison to a choice
Further, this experiment expanded on ways to circumvent the
between cocaine or novelty conditioned rewards, this study reveals
limitation of the all-or-none effect common to place conditioning
differences that may not be detectable in a standard place condi-
by demonstrating differences in the associative strength of 7.5, 20,
tioning protocol.
and 30 mg/kg cocaine. More important, these findings were not
Previously, we demonstrated that novelty competed with the
due to a stimulus generalization account or by differences in
conditioned rewarding effects of 7.5 mg/kg cocaine (Reichel &
activity impacting compartment choice.

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REICHEL AND BEVINS
Experiment 2
Habituation, Cocaine Place Conditioning, and
Competing Conditioning
Retention of Conditioned Novelty Reward
The procedures used in these phases were identical to those
The previous experiment determined the extent that novelty
described for Experiment 1 except that rats were assigned to one of
conditioned reward competed with cocaine conditioned stimuli.
three retention conditions (1, 14, or 28 days) and the dose of
More important, this competition differed according to the dose of
cocaine was 10 mg/kg.
cocaine. Competition was complete with 7.5 mg/kg cocaine on
both the drug and drug free tests. For the 20 mg/kg group com-
Drug Free and Drug Challenge Test Days
petition only existed on the drug free test. Due to this dissociation,
we incorporated another dose of cocaine that is widely used in the
The procedures used to test for preference were similar to those
field to even more fully characterize the competition seen between
described previously except the drug free tests occurred 1, 14, or
novelty and cocaine-conditioned reward. Thus, Experiment 2 es-
28 days after completion of the competing conditioning phase; the
tablished the initial place preference with 10 mg/kg cocaine and
drug challenge tests occurred 24 hr after the drug free retention test
determined whether novelty’s ability to compete with cocaine
(i.e., Day 2, 15, or 29).
persists or if the initial drug preference returned after a period of
abstinence.
Data Analysis
The conditioned rewarding effects of novelty compete with
those of cocaine when tested 24 to 48 hr (drug-free and drug
One of the goals of this experiment was to extend the findings
challenge tests, respectively) later (Reichel & Bevins, 2008).
of the dose effect (i.e., first experiment) to 10 mg/kg cocaine. To
Learning theories based on the primacy and recency effects predict
this end, rats assigned to the shortest retention interval (i.e., 1 and
that this competition might not survive a long delay between the
2 day drug free and drug challenges, respectively) were condi-
last novelty exposure and subsequent testing. According to the
tioned and tested separately than the longer retention interval
recency effect, training histories occurring closer in time have a
groups; therefore, these data are presented separately. The data
greater impact on behavior relative to earlier training histories
were analyzed as previously described.
(e.g., Miller & Escobar, 2003). According to this theory, novelty
rats would be expected to spend more time in the novelty-paired
Results
compartment because learning that occurred in Phase 2 (i.e., nov-
elty conditioning) would be more stable because this information
Habituation.
Prior to cocaine conditioning, rats did not ex-
occurred temporally closer to test day than learning that occurred
hibit a bias toward one particular stimulus (holes vs. rods) over the
in Phase 1 (i.e., cocaine conditioning). However, it is possible that
other. The mean time ( SEM) spent in the holes and rods com-
novelty rats may spend more time in the cocaine-paired compart-
partments was 259.2 ( 6.58) and 264.2 ( 5.45), respectively.
ment after longer retention intervals because as retention intervals
Activity scores were 35.3 ( 1.05) on the holes and 36.6 ( 1.28)
increase the recency effect subsides and is often replaced by a
on the rods.
primacy effect (Miller & Escobar, 2003; Urushihara, Wheeler, &
Place conditioning.
Figure 4 shows the time spent in each
Miller, 2004). With this in mind, the purpose of this experiment
compartment for rats conditioned with 10 mg/kg cocaine and
was to test for the competition between cocaine and novelty
tested 24 and 48 hr (drug free and drug challenge, respectively)
conditioned rewards at 1-, 14-, and 28-day retention intervals.
after competing conditioning. Control rats (n
13, left graph)
Figure 4.
Mean time ( SEM) spent in seconds in each compartment for rats conditioned with 10 mg/kg
cocaine in the control (left graph) and novelty (right graph) conditions on the three tests of place conditioning
in Experiment 2. PC
place conditioning; DF
drug free; DC
drug challenge.
Indicates significant
difference between compartments.

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COCAINE CONDITIONED REWARD SENSITIVITY
147
preferred the cocaine-paired compartment on all 3 test days, main
right graph), in contrast, only preferred the cocaine-paired side on
effect of side, F(1, 12)
13.65, p
.003. Novelty rats (n
13,
the initial test of cocaine (10 mg/kg) place conditioning, Side
right graph), in contrast, only preferred the cocaine-paired side on
Test interaction, F(2, 22)
3.45, p
.05, Tukey’s post hoc
the initial test of cocaine (10 mg/kg) place conditioning, Side
p
.05.
Test interaction, F(2, 24)
13.83, p
.001. Tukey’s post hoc
The lower panel (Figure 5B) shows the amount of time spent in
comparisons show that more time was spent in the cocaine-paired
each compartment for rats that were tested at 28 and 29 days (drug
compartment than the unpaired compartment on the initial day of
free and drug challenge, respectively) after novelty conditioning.
place conditioning ( p
.05).
Control rats (n
11, lower left graph) did not maintain compart-
Figure 5 shows the time spent in each compartment for rats that
ment preferences as there were no significant effects. Likewise,
were tested at longer retention intervals. The top panel (Figure 5A)
novelty rats (n
12, lower right graph), did not maintain com-
shows the data for rats that were tested at 14 and 15 days (drug free
partment preferences as the main effect of side and Side
Test
and drug challenge, respectively) after completing the novelty
interaction were not significant. To confirm that preferences ex-
conditioning phase. Control rats (n
12, upper left graph) pre-
isted on the test of cocaine place conditioning separate paired t
ferred the cocaine-paired compartment on the initial test of place
tests were conducted for each group. Indeed, both groups preferred
conditioning and the drug free challenge, which is supported by a
the cocaine-paired side, control, t(10)
3.60, p
.005, novelty,
main effect of side, F(1, 11)
5.3, p
.042. A paired t test
t(11)
2.76, p
.02.
between time spent in the paired versus unpaired compartment
Activity.
Figure 6A and B shows the activity data for the
confirmed that on the drug challenge test time was distributed
novelty and control groups tested at the three retention intervals.
equally between compartments, t
1. Novelty rats (n
12, upper
For rats in the shortest retention group (left graph), there was a
Figure 5.
Time spent (M
SEM) in each compartment for rats in the control and novelty groups for the three
tests of place conditioning (PC) in Experiment 2. Drug free (DF) testing occurred 14 and 28 days after
conditioning and drug challenge (DC) testing occurred 15 and 29 days after conditioning. Panel A depicts data
from rats tested at 14- and 15-day retention intervals and Panel B shows the 28- and 29-day retention intervals.
Control groups are in the left column and novelty groups are in the right.
Indicates significant difference
between compartments.

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148
REICHEL AND BEVINS
Figure 6.
Shows activity scores (M
SEM) for rats tested at different retention intervals on the three tests of
conditioning in Experiment 2. Panel A depicts the shortest retention interval in which drug free (DF) and drug
challenge (DC) tests occurred 24 and 48 hr, respectively, after the novelty conditioning phase. Panel B shows
activity scores for the longer retention intervals. Specifically, drug free testing occurred 14 and 28 days after
conditioning and drug challenge testing occurred 15 and 29 days after conditioning. PC
place conditioning.
Indicates significant difference on the drug challenge test in comparison to the drug free test for both groups.
main effect of test, F(2, 48)
7.13, p
.002. However, post hoc
ditioning phase and the subsequent test days. Thus, the retention
comparisons did not reveal any group differences. For rats tested
interval for cocaine place conditioning in this study is the retention
at the longer retention intervals, there was a main effect of test,
interval plus 1 test day plus the 8 days of novelty conditioning—23
F(2, 48)
61.16, p
.001. Specifically, a cocaine challenge
and 37 days. This finding is consistent with Mueller and Stewart’s
occurring 15 or 29 days after novelty conditioning resulted in
(2000) report that cocaine conditioned place preferences are main-
elevated activity in comparison to a drug free challenge on the
tained 4 (28 days) but not 6 (42 days) weeks postconditioning. We
preceding day (Tukey, p
.05).
should also note that retention of cocaine place conditioning was
likely weakened by the brief extinction (i.e., CS presented without
Discussion
the US) built into the experimental design. Rats in the control and
novelty conditions during the novelty-conditioning phase received
In the previous experiment, the doses of cocaine tested were 7.5,
four 10-min sessions of the previously cocaine-paired floor in the
20, and 30 mg/kg cocaine. That experiment identified the upper
absence of any cocaine. Thus, the impact of the prolonged reten-
limit (i.e., no competition at 30 mg/kg cocaine) of the extent that
tion interval in combination with some extinction of the floor
the conditioned rewarding effects of novelty could compete with
CS-cocaine association likely weakened the compartment prefer-
those of cocaine, and identified a dissociation in that competition
ence for the cocaine-paired side.
between 7.5 and 20 mg/kg cocaine. Specifically, novelty competed
A general question prompted by the present research is why the
with 7.5 mg/kg cocaine on both tests, yet novelty competed with
behavioral effects of the conditioned rewarding effects of novelty
20 mg/kg cocaine only on the drug free test. The current experi-
or cocaine do not survive indefinitely— especially novelty, given
ment suggests that the conditioned rewarding effects of 10 mg/kg
that there was no extinction (of the novelty paired compartment)
cocaine are more similar to 7.5 than 20 mg/kg cocaine. That is,
novelty competed with the conditioned rewarding effects of 10
experience before testing. There are two notable theoretical ac-
mg/kg cocaine on the drug free and drug challenge test. Thus,
counts that could explain the lack of effect of either novelty or
evidence of competition on both test days for the 7.5 and 10 mg/kg
cocaine after a long retention interval: stimulus generalization or
group suggests that these two moderate doses of cocaine have
the context-change account of forgetting. According to the stimu-
similar appetitive and stimulus properties as measured in this
lus generalization account, recall of detailed stimulus properties
version of a place conditioning task. Conversely, this pattern of
within a learning situation is transient because specific attributes of
results with 10 mg/kg cocaine differs from 20 mg/kg; the condi-
stimuli are forgotten (Riccio, Ackil, & Burch-Vernon, 1992). This
tioned rewarding effects of this higher dose were more robust than
loss of detail regarding the learning situation leads to greater
novelty when tested in the cocaine state.
generalization across learning situations. Albeit speculative, ap-
Novelty conditioned reward also competed with the conditioned
plied to the present experiment there could be recall of a context-
rewarding effects of cocaine after a 14 day retention interval on the
reward association remaining, but not recall of the specific flooring
drug free test. Even though these rats spent similar amounts of time
that is the only distinct stimulus in our conditioning situation.
in both compartments on the drug challenge test, the interpretation
Alternatively, the context-change account suggests that percep-
of this test is negated because the control group did not maintain
tion of contextual cues present at the time of conditioning change
a preference for the cocaine compartment in the drug state. Perhaps
with the passage of time. This shift is responsible for what appears
a weakened compartment preference could not survive additional
to be forgetting of stimulus attributes (Bouton, Nelson, & Rosas,
extinction of the cocaine-paired cues occurring on the drug free test.
1999). This account conceptualizes the context as including the
The control rats did, however, retain a cocaine preference 14 days
internal state of the animal at the time of conditioning and testing
but not 28 days post novelty conditioning. Recall that the retention
(Bouton et al., 1999). For example, rats tested at longer retention
interval in our study refers to the time between the novelty con-
intervals are typically older, larger, and have experienced differ-

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COCAINE CONDITIONED REWARD SENSITIVITY
149
ences in handling than rats tested at shorter retention intervals,
The present research examined the import of intensity or sa-
which may change perception of the testing context. This problem
lience of the cocaine US while holding constant the intensity of the
can be overcome by testing subjects at the same time; however the
novel object US. Experiments that change the saliency of the
age at which conditioning occurs varies thus introducing a differ-
novelty US by varying the intensity of the novel object exposure
ent problem. Seemingly, any exploration of retention intervals is
may result in more robust competition between the two rewards
fraught with either a “day-of-test” or “day-of-training” confound
and have an even more profound influence on choice behaviors
(Bouton et al., 1999). Regardless, in the current experiment per-
maintained by drug conditioning. Indeed, reducing the intensity of
ceived aspects of the conditioning and testing experience may have
the novel objects by reducing the amount of access time decreased
changed over time from both external and internal sources, which
preferences conditioned by novel objects (Bevins et al., 2002).
may have impacted compartment choice on the drug free tests.
Whether the converse is true in regards to reward competition
Albeit speculative, the theoretical accounts described in the
remains unexplored.
previous paragraph can be related to a neural account proposed by
In the current experiments, rats experienced the rewarding aspects
Rosenbaum, Winocur, and Moscovitch (2001). According to that
of systemic cocaine by alternating daily placements into the chamber.
neural theory, as context specific memories become consolidated
Thus, an association is presumably formed between the physiological
by the hippocampus they loose specificity over time (Rosenbaum
effects of cocaine (US) and the features of the environment (i.e.,
et al., 2001). More so, with the passage of time, Rosenbaum et al.
the CS). In contrast, to experience novelty reward the rat must
(2008) posited that the link between the event and the actual
perceive, approach, and interact with the object. Thus, an associ-
context in which an event occurred becomes less important than
ation may occur between the rewarding aspects of novelty (US)
the memory itself. A place conditioning procedure relies on the
and the features of the objects (CS) and/or the environment (CS) in
formation of a conditioned association between the rewarding
this situation. In other words, adding the object on a conditioning
aspects of the stimulus of interests and the contextual cues of the
day may be thought of as creating a compound CS composed of
environment. In our study, the contexts become associated with the
the environment CS plus the object CS. In essence, the stimulus
rewarding aspects of cocaine and novelty. Over time, it is possible
aspects of the object on a given day may somewhat overshadow
that the link between a preference for the paired environment and
conditioning to the environment CS. Further, on the test day only
the actual physical feature of the context becomes less important
the environment CS is assessed. If so, such overshadowing and
than the memory of the preference itself. Although not tested, in
then testing of only part of the relevant stimulus elements func-
our experiment this neural account takes into consideration a
tioning as a CS limits the impact of conditioned novelty reward on
change in perception of conceptual cues and generalization among
choice in the present protocol.
external stimuli.
Exposure to novel stimuli during treatment may have clinical
To conclude, this experiment demonstrated that the conditioned
utility by acting as an effective substitute for drug reward (Bevins,
rewarding effects of novelty competed with those of cocaine
2001; Cain, Saucier, & Bardo, 2005; Dellu, Piazza, Mayo,
following a 14-day retention interval in the drug free state. The
LeMoal, & Simon, 1996; D’Silva, Harrington, Palmgreen, Dono-
lack of competition following a 28-day retention interval is subject
hew, & Lorch, 2001). The ability of novelty to compete with
to interpretation by different theoretical accounts. When consid-
cocaine may have use as a behavioral substitution strategy because
ered together, the pattern of compartment preferences expressed in
environment— drug associations formed while abusing the sub-
this experiment suggests that our model is limited as designed.
stance continually impact choice behaviors. Providing alternative-
Despite this limitation in design, we identified a window of op-
learning histories, including new nondrug associations during the
portunity for conditioned rewards to compete for control over
intervention program may change choice behavior after an envi-
choice behavior. Strategies to increase this window should be of
ronment— drug association is formed. These studies indicate that
interest and will likely prove useful for studying competition
novelty as a behavioral substitution strategy may have more suc-
among conditioned reward (see below).
cess with mild users rather than heavier users. More so, imple-
menting novelty may be more effective in the earlier rather than
later stages of treatment.
General Discussion
Alternative choices presented to the addict during times of
abstinence may increase the likelihood of discontinued drug use.
This study demonstrates that the conditioned rewarding effects
The use of novel experiences as an adjunct for behavior treatments,
of novelty can compete with those of moderate cocaine doses (e.g.,
like contingency management, may be one option available to
7.5 and 10 mg/kg cocaine) whether the drug is present in the
promote nondrug choices in addicts. This approach may be par-
central nervous system. However, with higher and presumably
ticularly relevant to individuals classified as high novelty and/or
more rewarding doses, competition only occurs in the absence of
sensation seekers (Cloninger, 1987; Zuckerman, 1994). People that
drug (20 mg/kg) or not at all (30 mg/kg). More important, this
seek out novel and high-risk situations (i.e., high-sensation seek-
competition does not seem to be permanent. These experiments
ers) report high incidences of drug use (Palmgreen, Donohew,
varied cocaine dose and retention interval while holding the nov-
Lorch, Hoyle, & Stephenson, 2001; Stephenson, 2003; Zuckerman
elty stimulus constant during the second experimental phase.
& Kuhlman, 2000). More so, individuals fitting into this category
Throughout both experiments the order, number, and time of the
(i.e., high-sensation seekers) generally participate in more extra-
novel object presentations were consistent between experiments
curricular activities than those classified as low-sensation seekers
and our previous report (Reichel & Bevins, 2008). And, indeed,
(D’Silva et al., 2001). In fact high-sensation seekers tend to choose
these procedures reliably condition compartment preferences in
leisure activities classified as action-adventure (e.g., scuba diving,
our laboratory (Besheer, Jensen, & Bevins, 1999).
mountain climbing, white water rafting, kayaking, rock climbing,

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150
REICHEL AND BEVINS
canoeing, snow skiing) and conflict-combat (e.g., survival games,
Corbit, L. H., & Balleine, B. W. (2005). Double dissociation of basolateral and
role playing, martial arts, paint ball) related activities (D’Silva et
central amygdala lesions on the general and outcome-specific forms of
al., 2001). In regards to the present discussion, treatment programs
Pavlovian-instrumental transfer. Journal of Neuroscience, 25, 962–970.
implementing novel rewards targeted to those individuals that have
Delamater, A. R., & Holland, P. C. (2008). The influence of CS–US
high novelty/sensation seeking tendencies may offer addicts the
interval on several different indices of learning in appetitive condition-
ing. Journal of Experimental Psychology: Animal Behavior Processes,
opportunity (e.g., with vouchers) to participate in one of the
34, 202–222.
activities mentioned previously in the hopes of maintaining absti-
Dellu, F., Piazza, P. V., Mayo, W., LeMoal, M., & Simon, H. (1996).
nence. In conclusion, these studies provide empirical support for
Novelty-seeking in rats—Biobehavioral characteristics and possible re-
the idea that drug treatment programs may use novelty to enhance
lationship with the sensation-seeking trait in man. Neuropsychobiology,
intervention programs by providing new learning histories that are
34, 136 –145.
incompatible with drug use.
D’Silva, M. U., Harrington, N. G., Palmgreen, P., Donohew, L. D., &
Lorch, E. P. (2001). Drug use prevention for the high sensation seeker:
The role of alternative activities. Substance Use & Misuse, 36, 373–385.
References
Garcia-Rodriquez, O., Secades-Villa, R., Higgins, S. T., Fernandez-
Hermida, J. R., Carballo, J. L., Perez, J. M. E., & Diaz, S. A. (2009).
Bardo, M. T., & Bevins, R. A. (2000). Conditioned place preference: What
Effects of voucher-based intervention on abstinence and retention in an
does it add to our preclinical understanding of drug reward? Psychop-
outpatient treatment for cocaine addiction: A randomized controlled
harmacology, 153, 31– 43.
trial. Experimental and Clinical Psychopharmacology, 17(3), 131–138.
Bardo, M. T., Donohew, R. L., & Harrington, N. G. (1996). Psychobiology
Gremel, C. M., & Cunningham, C. L. (2007). Role of test activity in
of novelty seeking and drug seeking behavior. Behavioural Brain Re-
ethanol-induced disruption of place preference expression in mice. Psy-
search, 77, 23– 43.
chopharmacology, 191, 195–202.
Bardo, M. T., & Dwoskin, L. P. (2004). Biological connection between
Groblewski, P. A., Bax, L. S., & Cunningham, C. L. (2008). Reference-
novelty- and drug-seeking motivational systems. In R. A. Bevins &
dose place conditioning with ethanol in mice: Empirical and theoretical
M. T. Bardo (Eds.), Nebraska symposium on motivation: Vol. 50. Mo-
analysis. Psychopharmacology. doi:10.1007/s00213– 008-1251–3
tivational factors in the etiology of drug abuse (pp. 127–158). Lincoln:
Konorski, J. (1967). Integrative activity of the brain. Chicago, IL: Univer-
University of Nebraska Press.
sity of Chicago Press.
Bardo, M. T., Rowlett, J. T., & Harris, M. J. (1995). Conditioned place
Mattson, B. J., Williams, S., Rosenblatt, J. S., & Morrell, J. I. (2001). Com-
preference using opiate and stimulant drugs: A meta-analysis. Neuro-
parison of two positive reinforcing stimli: Pups and cocaine throughout the
science and Biobehavioral Reviews, 19, 39 –51.
postpartum period. Behavioral Neuroscience, 115, 683– 694.
Barr, G. A., Paredes, W., & Bridger, W. H. (1985). Place conditioning with
Miller, R. R., & Escobar, M. (2003). Learning: Laws and models of basic
morphine and phencyclidine: Dose dependent effects. Life Sciences,
learning. In C. R. Gallistel (Ed.), Steven’s handbook of experimental
36(4), 363–368.
psychology: Vol. 3. Learning, motivation, and emotion (Vol. 3, pp.
Besheer, J., Jensen, H. C., & Bevins, R. A. (1999). Dopamine antagonism
42–102). New York, NY: Wiley.
in a novel-object recognition and a novel-object place conditioning
Mueller, D., & Stewart, J. (2000). Cocaine-induced conditioned place
preparation with rats. Behavioural Brain Research, 103(1), 35– 44.
preference: Reinstatement by priming injections of cocaine after extinc-
Bevins, R. A. (2001). Novelty seeking and reward: Implications for the
tion. Behavioural Brain Research, 115(1), 39 – 47.
study of high-risk behaviors. Current Directions in Psychological Sci-
ence, 10, 189 –193.
National Research Council. (1996). Guide for the care and use of labora-
Bevins, R. A., Besheer, J., Palmatier, M. I., Jensen, H. C., Pickett, K. S.,
tory animals. Washington, DC: National Academy Press.
& Eurek, S. (2002). Novel-object place conditioning: behavioral and
O’Dell, L. E., Khroyan, T. V., & Neisewander, J. L. (1996). Dose-
dopaminergic processes in expression of novelty reward. Behavioral
dependent characterization of the rewarding and stimulant properties of
Brain Research, 129(1–2), 41–50.
cocaine following intraperitoneal and intravenous administration in rats.
Bevins, R. A. (2005). The reference-dose place conditioning procedure
Psychopharmacology, 123, 144 –153.
yields a graded dose-effect function. International Journal of Compar-
Pace-Schott, E. F., Morgan, P. T., Malison, R. T., Hart, C. L., Edgar, C.,
ative Psychology, 18, 101–111.
Walker, M., & Stickgold, R. (2008). Cocaine users differ from normals
Bevins, R. A., & Cunningham, C. L. (2006). Place conditioning: A meth-
on cognitive tasks which show poorer performance during drug absti-
odological analysis. In M. Anderson (Ed.), Tasks and techniques: A
nence. The American Journal of Drug and Alcohol Abuse, 34, 109 –121.
sampling of methodologies for the investigation of animal learning,
Palmgreen, P., Donohew, L., Lorch, E. P., Hoyle, R. H., & Stephenson,
behavior, and cognition. Hauppauge, NY: Nova Science.
M. T. (2001). Television campaigns and adolescent marijuana use: Tests
Bouton, M. E., Nelson, J. B., & Rosas, J. M. (1999). Stimulus generalization,
of sensation seeking targeting. American Journal of Public Health, 91,
context change, and forgetting. Psychological Bulletin, 125, 171–181.
292–296.
Cain, M. E., Saucier, D. A., & Bardo, M. T. (2005). Novelty seeking and
Patkina, N. A., & Zvartau, E. E. (1998). Caffeine place conditioning in rats:
drug use: Contribution of an animal model. Experimental and Clinical
Comparison with cocaine and ethanol. European Neuropsychopharma-
Psychopharmacology, 13, 367–375.
cology, 8(4), 287–291.
Cain, M. E., Smith, C. M., & Bardo, M. T. (2004). The effect of novelty
Pavlov, I. P. (1927). Conditioned reflexes. London, England: Oxford
on amphetamine self-administration in rats classified as high and low
University Press.
responders. Psychopharmacology, 176, 129 –138.
Reichel, C. M., & Bevins, R. A. (2008). Competition between the condi-
Cloninger, C. R. (1987). A systematic method for clinical description and
tioned rewarding effects of cocaine and novelty. Behavioral Neuro-
classification of personality variants. A proposal. Archives of General
science, 122, 140 –150.
Psychiatry, 44, 573–588.
Rescorla, R. A. (2004). Spontaneous recovery. Learning and Memory, 11,
Colzato, L. S., van den Wildenberg, W. P. M., & Hommel, B. (2008).
501–509.
Reduced spontaneous eye blink rates in recreational cocaine users:
Riccio, D. C., Ackil, J., & Burch-Vernon, A. (1992). Forgetting of stimulus
Evidence for dopaminergic hypoactivity. PLoS ONE, 3, e3461. doi:
attributes: Methodological implications for assessing associative phe-
101.1371/journal.pone0003461
nomena. Psychological Bulletin, 112, 433– 445.

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