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BRIEF COMMUNICATIONS
Delayed Extinction and Stronger Reinstatement of Cocaine Conditioned
Place Preference in Adolescent Rats, Compared to Adults
Heather C. Brenhouse and Susan L. Andersen
McLean Hospital
Adolescence is a transitional period during development that is associated with a greater likelihood of
addiction to drugs than any other age. One possibility for this observation is that learned associations
between the rewarding experience of drugs and drug-related cues may produce greater motivational
salience, and thus are more difficult to extinguish. Using an unbiased place-conditioning paradigm with
two doses of cocaine (10 mg/kg or 20 mg/kg), the authors show here that adolescents require 75 ⫾ 17%
more extinction trials than adults to extinguish cocaine place-preferences. Furthermore, once extin-
guished, adolescents display a greater preference for a previously cocaine-paired environment upon
drug-primed reinstatement compared with adults. These results suggest that adolescent vulnerability to
addiction involves robust memories for drug-associated cues that are difficult to extinguish. Therefore,
drug-addicted adolescents may have a higher risk of relapse than adults, leading to greater prevalence of
addiction in this population.
Keywords: adolescent, extinction, reinstatement, cocaine, place-conditioning
Drug addiction is a chronic disorder characterized by compul-
sive drug craving, seeking, and use that persist despite severe
adverse consequences. Most experimentation with drugs occurs
during adolescence and early adulthood (Compton, Grant, Col-
liver, Glantz, & Stinson, 2004; SAMHSA, 1999; Spear, 2000b).
Although increased social behavior, novelty seeking, and risk-
taking may underlie experimentation (Laviola, Macri, Morley-
Fletcher, & Adriani, 2003), a disproportionate number of those that
experiment during adolescence become addicted relative to any
other age group. O’Brien and Anthony (O’Brien & Anthony,
2005) report a fourfold higher risk for addiction if drug exposure
occurs during adolescence (12–14 years of age) compared to
exposure during young adulthood (21–25 years of age). The mech-
anisms that underlie this window of vulnerability are still unclear.
Addiction represents pathological alterations in systems that
normally serve reward-related learning. Normal developmental
brain changes that play a role in these behaviors contribute to a
unique susceptibility to drug abuse with exposure in adolescence
(Spear, 2000a), and may underlie a vulnerability to lasting pertur-
bations in circuitry if drug abuse occurs (Crews, He, & Hodge,
2007). These key changes include increases in prefrontal cortex
(PFC) dopamine (DA) fiber density (Kalsbeek, Voorn, Buijs, Pool,
& Uylings, 1988) as well as overproduction of PFC DA receptors
in rats (Andersen, Thompson, Rutstein, Hostetter, & Teicher,
2000). The PFC mediates the attribution of salience to learned cues
as well as goal-directed behaviors (Rebec & Sun, 2005; Ventura,
Morrone, & Puglisi-Allegra, 2007), and therefore these changes
may place adolescents at risk for enhanced drug-cue associations
and drug-seeking behaviors.
Place conditioning provides a measure of drug seeking by
assessing an animal’s preference for (or aversion to) environmen-
tal cues associated with drug-induced effects. Using this proce-
dure, cocaine is exclusively paired with a previously neutral en-
vironment whereas a second environment is exclusively paired
with vehicle (Carlezon, 2003). The animal is subsequently allowed
to move freely between the two environments—in a drug free
state—and the time spent in the drug-paired and nondrug paired
environments is measured. Time spent in the drug-paired environ-
ment is interpreted as a preference, whereas time spent away from
the environment is interpreted as an aversion. These Pavlovian-
acquired preferences or aversions to the environmental cue are
believed to reflect conditioned incentive properties (Robinson &
Berridge, 2003). Several behavioral studies indicate that memory
for conditioned place preference (CPP) is subject to extinction, as
nonrewarded exposure to environmental contexts previously
paired with rewarding drug treatments reduces subsequent CPP
(Bardo, Neisewander, & Miller, 1986; Calcagnetti & Schechter,
1993; Mueller & Stewart, 2000; Schroeder & Packard, 2004). CPP
memory is also subject to reconsolidation after extinction, result-
ing in reinstatement of drug seeking (Balda, Anderson, & Itzhak,
2006; Sanchez, Bailie, Wu, Li, & Sorg, 2003).
In adult male rats, a cocaine place preference is effectively
established for 20 mg/kg cocaine (Bardo et al., 1986). Adolescent
rats have been reported to be more sensitive to the place condi-
tioning effects of cocaine, showing preferences after conditioning
with lower doses (5 mg/kg) than adults (Badanich, Adler, &
Kirstein, 2006). These reports indicate a difference in sensitivity to
Heather C. Brenhouse and Susan L. Andersen, McLean Hospital, Har-
vard Medical School.
Correspondence concerning this article should be addressed to Heather
C. Brenhouse, PhD, McLean Hospital, Harvard Medical School, 115 Mill
St., Belmont, MA 02144. E-mail: hbrenhouse@mclean.harvard.edu
Behavioral Neuroscience Copyright 2008 by the American Psychological Association
2008, Vol. 122, No. 2, 460 – 465 0735-7044/08/$12.00 DOI: 10.1037/0735-7044.122.2.460
460
the conditioning properties of cocaine as a function of age. In
contrast, Campbell, Wood, and Spear (2000) reported no differ-
ences in CPP using a biased paradigm for the same moderate dose
(10 mg/kg) of cocaine between adolescents and adults. However,
males and females were included in their assessment. Clinical
research suggests that adolescence is indeed a critical period when
motivational conditioning is heightened. For example, 66% of
adults who complete inpatient treatment for chemical dependence
maintain total abstinence from alcohol or other drugs during the
year after treatment, compared to only 42% abstinence rate re-
ported for adolescent inpatient programs with similar treatment
philosophy and geographic locations (Harrison & Hoffmann,
1989).
The current study was based on the hypothesis that adolescent
vulnerability to addiction involves a developmental state, based on
neurobiological changes (Brenhouse & Andersen, 2007), that is
primed to assign high salience to reward-related cues, and to retain
the motivational salience of these cues at the expense of competing
information. Given the unique neural substrates mediating learning
and motivation, as well as evidence that suggests adolescents are
particularly vulnerable to addiction, we examined whether extinc-
tion of drug seeking is differentially achieved in adolescent and
adult rats. We used a place-conditioning procedure to test whether
adolescents have a greater latency than adults to extinguish a CPP
for 10 mg/kg or 20 mg/kg cocaine. Additionally, we investigated
whether reinstatement of drug seeking after extinction differs
between these two age groups.
Method
Subjects
Male Sprague–Dawley rats were obtained from Charles River
(Boston). Adolescents were P38 at the start of conditioning and
adults were P77. Food and water were available ad libitum in
constant temperature and humidity conditions on a 12-hr light:dark
cycle (light period 0700–1900). All experiments were conducted
in accordance with the 1996 Guide for the Care and Use of
Laboratory Animals (NIH), and were approved by the Institutional
Animal Care and Use Committee at McLean Hospital. Rats were
given a minimum of 1 week to acclimate to our facilities before
any testing began, and were handled for a minimum of 3 days
before testing.
Adolescent and adult rats were conditioned to 10 or 20 mg/kg
(i.p.) cocaine and tested for CPP, using an unbiased place-
conditioning paradigm (Carlezon, 2003). Conditioning occurred in
a three-chamber apparatus, consisting of two large (24 ⫻ 18 ⫻ 33
cm) side compartments and a small (12 ⫻ 18 ⫻ 33 cm) middle
gray compartment (Med Associates, Georgia, VT). Compartments
differed in floor texture, wall coloring, and lighting. Rats were
screened for 30 min on Day 1, during which animals were allowed
to freely explore the entire apparatus after a 5-min adaptation
confined to the middle gray compartment. Two rats with an initial
preference to one side (⬎18 of 30 min) were eliminated from
further testing, and groups were organized such that average base-
line preferences were further minimized (Graham, Hoppenot, Hen-
dryx, & Self, 2006; Mueller & Stewart, 2000). Two days of
conditioning (Days 2 and 3) with two sessions per day were
conducted, during which rats were injected with saline (1 ml/kg,
i.p.) in the morning and placed in one side for 1 hr, and 4 hrs later
injected with one of two doses of cocaine (10 or 20 mg/kg, i.p.;
n ⫽ 6 – 8) and placed into the opposite side for 1 hr. This order of
conditioning ensured against an association with symptoms of
dysphoria (e.g., acute drug withdrawal) with the nondrug environ-
ment during the afternoon session (Carlezon, 2003). On the fourth
day, rats were permitted to freely explore the entire apparatus for
30 min in a drug-free state to test for CPP. Preference scores were
calculated by determining the ratio of the time spent in the drug-
paired side to the total time spent in both paired and unpaired sides.
Twenty-four hours after this initial test, rats were again introduced
to the entire apparatus in a drug-free state for 30 min, and time
spent in each chamber was recorded. This test was repeated daily
until each animal achieved extinction, defined as a 50% reduction
of time spent in the drug-paired compartment compared to the
initial CPP test for two consecutive days (Sanchez et al., 2003).
Based on group averages, a 50% reduction in time spent in the
drug-paired chamber implies no preference such as that observed
during baseline measures. Twenty-four hours after the last extinc-
tion trial, each rat was administered 5 mg/kg cocaine (i.p.) and
reintroduced to the apparatus with free access for 30 min to test for
drug-primed reinstatement of CPP. There was 5 mg/kg chosen as
a low priming dose that has been commonly used for reinstatement
of CPP (e.g., (Mueller & Stewart, 2000; Sanchez et al., 2003;
Zavala, Weber, Rice, Alleweireldt, & Neisewander, 2003) and is
consistent with previous studies on reinstatement after adolescent
cocaine exposure (Balda et al., 2006).
Analyses of variance (ANOVAs) were performed to determine
the effects of age and dose on the acquisition, extinction, and
reinstatement of place preference. Regression analyses were con-
ducted to determine whether initial preference scores on test day
were correlated with the number of extinction trials required to
reach criterion, or with the degree of reinstatement. Because of a
significant correlation, ANCOVA (with initial preference score
from test day as the covariate) was used to determine the effects of
age and dose on the number of days required to extinguish drug
seeking. Student’s t tests were performed for pairwise comparisons
when noted. Only animals that formed a preference for the drug-
paired chamber, designated by a greater preference score on test
day than on screen day (8/8 adolescents at 20 mg/kg; 6/6 adoles-
cents at 10 mg/kg); 8/8 adults at 20 mg/kg; 3/8 adults at 10 mg/kg)
were included in further extinction testing and in all analyses.
Results
Both adolescents and adults formed reliable place preferences
for 20 mg/kg cocaine (see Figure 1). In contrast, when a 10 mg/kg
conditioning dose was given, fewer than half of the adults (3/8)
formed a conditioned preference for the drug-paired chamber,
whereas all of the adolescents formed a conditioned preference.
Repeated testing was then performed to assay extinction of these
preferences.
Collapsed across ages, the number of trials necessary to reach
extinction was found to correlate with initial preference scores
(R
2
⫽ 0.39; p ⬍ .01), and therefore, ANCOVA was performed to
determine whether stronger initial preferences for the drug-paired
environment better predicted the latency to extinguish than age.
When accounting for the variance because of initial preference
scores with an ANCOVA, adolescents still required more extinc-
461
BRIEF COMMUNICATIONS
tion trials than adults to extinguish drug-seeking behavior, with a
significant main effect of age (F(1, 19) ⫽ 7.4; p ⬍ .05; Figure 1).
Specifically, adolescents took 8.7 ⫾ 0.7 days to reach extinction,
whereas adults reached criterion within 5 ⫾ 0.6 days (collapsed
across dose, covaried means). There was no significant interaction
between age and dose on the number of days to extinguish.
When animals were conditioned to 20 mg/kg cocaine, prefer-
ence scores across extinction trials were significantly different
between ages (F(1, 14) ⫽ 31.8; p ⬍ .01; see Figure 1). However,
when animals were conditioned to 10 mg/kg cocaine, the three (of
eight) adults that formed an initial preference for the cocaine-
paired environment did not differ from adolescents in their pref-
erence scores throughout extinction.
Figure 2 illustrates that drug-primed reinstatement of CPP was
significantly affected by age (F(1, 14) ⫽ 5.1; p ⬍ .05). After
extinction was achieved, a priming injection with 5 mg/kg of
cocaine caused adolescents to spend more time in the previously
cocaine-paired chamber, compared to adults, regardless of the
conditioning dose. Both adolescents ( p ⬍ .01) and adults ( p ⬍
.05) displayed significant increases in preference scores between
the last extinction trial and the reinstatement trial after being
conditioned to 20 mg/kg of cocaine. However, only adolescents
conditioned to 10 mg/kg displayed significant reinstatement ( p ⬍
.05) whereas adults did not. No significant correlations were found
between either initial preferences or days to extinguish with degree
of reinstatement.
Discussion
Following acquisition of CPP for cocaine-paired environments,
adolescents took significantly (75% ⫾ 17) longer than adults to
extinguish these learned preferences. Adolescents were also more
vulnerable to drug-primed reinstatement of CPP after extinction,
displaying significant reinstatement for a lower conditioning dose
of cocaine than adults and spending more time than adults in a
previously drug-paired environment. These results suggest that, in
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Bsl Test E1 E3 E6 E9 E12
Extinction Days
b. 10 mg/kg cocaine
2
11
4
5
5
3
3
2
1
5
5
7.4 (1)
6 (2)
0.3
0.4
0.5
0.6
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0.8
0.9
Adolesc
Adult
a. 20 mg/kg cocaine
*
*
8
8
8
8
7
8
8
8
4
1
9 (1)
4 (1)
Preference Score
Figure 1. Adolescent rats require more extinction trials to extinguish
conditioned place preferences for cocaine, compared to adults. Top and
bottom graphs illustrate the acquisition and extinction of conditioned
preference for an environment paired with 20 mg/kg cocaine (A) or 10
mg/kg cocaine (B). Numbers at each data point represent the number of
animals that had not yet reached criterion and therefore remained in the
experiment. Shaded boxes represent means ⫾ SEM for adults that did not
form preferences for the drug-paired environment, and therefore were
excluded from further analyses. Preference scores represent the ratio of
time spent in the drug-paired chamber to total time spent in both paired and
unpaired chambers. Horizontal bars under each graph represent means ⫾
SEM of the number of days required to reach extinction criterion for
adolescent (filled) or adult (open) rats after conditioning to each dose of
cocaine.
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Adolesc Adult Adolesc Adult
Last Ext Trial
5 mg/kg cocaine
Preference Score
*
*
10 mg/kg 20 mg/kg
*
Figure 2. Reinstatement of conditioned place preference is achieved in
adolescents conditioned to either 10 or 20 mg/kg cocaine, while reinstate-
ment is achieved in adults only to environments paired with 20, but not 10
mg/kg cocaine. Bars represent means ⫾ SEM of preference scores on the
last extinction trial for each animal and after challenge with 5 mg/kg
cocaine (24 hr after last extinction trial).
462
BRIEF COMMUNICATIONS
an unbiased place-conditioning paradigm, adolescent rats form
preferences for a cocaine-paired environment that take longer to
extinguish than preferences formed by older adults.
The one other study we know of examining extinction and
reinstatement of cocaine CPP during development (Balda et al.,
2006) was conducted using mice and yielded similar propensities
for relapse after prepubertal exposure as reported here. However,
reinstatement was assessed later in adulthood, while the present
data is related to extinction and reinstatement within the adolescent
period. Additionally, adult mice failed to extinguish after 28 days
of intermittent, nonrewarded exposure to the context (Balda et al.,
2006), which is in contrast to other reports (Sanchez et al., 2003)
and ours that used daily extinction trials. Taken together, we report
that when adolescents and adults are directly compared, adoles-
cents show delayed extinction of cocaine-seeking behavior, and
may maintain stronger and more resilient preferences for drug-
paired cues during this stage. Differences in memory and recon-
solidation processes between these two age groups should be
examined more directly in future studies, and may reflect impor-
tant developmental changes in cue-processing brain regions such
as the amygdala and PFC (Andersen et al., 2000; Kerstetter &
Kantak, 2007; Quirk & Mueller, 2007)
Our findings are consistent with research in both humans and
animals demonstrating that adolescence is characterized by a par-
ticular vulnerability to drug abuse and addiction (Badanich et al.,
2006; Laviola, Wood, Kuhn, Francis, & Spear, 1995; O’Brien &
Anthony, 2005; Spear, 2000a). Addiction often occurs when drug-
paired cues are processed as salient events that motivate procure-
ment of more drug, while simultaneously solidifying memories
linked to the experience (Baler & Volkow, 2006). Increased sa-
lience attribution facilitates memory consolidation of drug-related
events (Baler & Volkow, 2006). Therefore, it is possible that
adolescents assign higher salience to drug-associated contexts,
making nonrewarded exposure to the drug-associated environment
less able to compete as a new memory. The paradigm of place
conditioning allows assessment of these incentive motivational
properties that endure in the absence of the direct, rewarding
effects of cocaine.
Adolescents have previously been reported to be more sensitive
to the conditioning effects of cocaine, forming preferences for
contexts associated with a lower dose (5 mg/kg) than those re-
quired for adults (Badanich et al., 2006). Our results support these
reports given that only three of eight 80-day-old male adults
conditioned with 10 mg/kg of cocaine formed a preference for the
drug-paired context. Therefore, this reveals an important caveat in
the comparison of P80 adults to adolescents at the 10 mg/kg dose
because the adults that formed conditioned place preferences may
represent an atypical sample compared to the majority of P80 rats
that did not form preferences. This small sample size of adults
resembled adolescents in the time required for extinction, yet did
not display significant reinstatement upon cocaine challenge. More
research on these apparent individual differences is needed, pos-
sibly involving early life experiences given the genetic homoge-
neity within strains.
Important differences exist between the paradigms used to as-
sess extinction, which perhaps depend more on the methodology
used to produce drug-seeking behaviors. This is highlighted in the
difference between the hypersensitivity to cocaine place condition-
ing and the hyposensitivity to the locomotor effects of cocaine
(Frantz, O’Dell, & Parsons, 2007), or the lack of age effects on
cocaine self-administration (Frantz, O’Dell, & Parsons, 2007; Ker-
stetter & Kantak, 2007). As described by Calcagnetti and
Schechter (1992), place conditioning pairs a drug with a cue-
specific environment, independent of the animal’s emitted operant
behavior. The resulting change in affective state, measured by
preference or aversion, is related to the reinforcing properties of
the drug. In contrast, self-administration depends on the reinforc-
ing effects of the drug itself and its ability to maintain responding.
Here, we measured the ability of animals to form drug-cue asso-
ciations, rather than examining the direct reinforcing effects of
cocaine in these animals. A recent study highlights this difference
between these two behavioral assays (Kerstetter & Kantak, 2007).
Although adolescents and adults self-administered comparable
levels of cocaine, conditioned-cue preferences to cocaine differed
as a function of age later in life.
A number of studies have shown that adolescents are more
sensitive to drug-associated environments than adults, although
sex, age of the subjects, and prior handling are important variables
to consider. For example, nicotine and alcohol elicit greater place
preferences in adolescents relative to adult rats (Belluzzi, Lee,
Oliff, & Leslie, 2004; Philpot, Badanich, & Kirstein, 2003; Vas-
tola, Douglas, Varlinskaya, & Spear, 2002). However, other place
conditioning studies using cocaine (Aberg, Wade, Wall, & Izen-
wasser, 2007; Campbell, Wood, & Spear, 2000) did not report
greater preferences in adolescents. Experimental differences may
account for these disparities. First, the sex of the animals is an
important factor to consider. Age differences in place conditioning
to 10 mg/kg cocaine are diminished if female rats are included in
the assessment, as females demonstrate a greater choice ratio for
the cocaine-associated side (Campbell et al., 2000). Similar results
are found in adult female mice, which also demonstrated greater
place preferences to cocaine-associated environments, in an unbi-
ased paradigm (Balda et al., 2006). Second, the age of the adult
used for comparison is important because of differences in cortical
maturation (e.g., Andersen et al., 2000; Brenhouse & Andersen,
2007), which is important for cue processing (Kalivas, Volkow, &
Seamans, 2005). Adults used in earlier studies were as young as 65
days old (Campbell et al., 2000), compared to the current study,
which used rats that were 80 days old. Third, prior handling seems
to influence the degree of place conditioning. For example, ado-
lescents at ages similar to those used in the present study failed to
show preferences for environments associated with 10 mg/kg of
cocaine (Aberg et al., 2007). However, methodological differences
may explain these disparities, because the animals had all been
previously handled and injected repeatedly with either MDMA or
saline for 7 days. Taken together, it should be noted that a wide
variety of place conditioning protocols have been used in the
existing literature and results may differ for several methodolog-
ical reasons such as sex, age, and prior handling.
Although a significant emphasis has been placed on the acqui-
sition of drug seeking, less attention has been paid to the extinction
of this process during adolescence. Extinction of nicotine self-
administration was found to be shorter in adolescents (Shram,
Funk, Li, & Le, 2007), which points again to distinctions in what
different behavioral assays measure. It appears from the present
data that the association between cocaine and cocaine-paired en-
vironments is retained longer in adolescents, compared to adults.
We propose that the delayed extinction observed in adolescence is
463
BRIEF COMMUNICATIONS
because of greater salience attribution to drug-paired cues, rather
than a greater “liking” of the drug. Indeed, when accounting for
individual correlations between higher initial preferences and time
to extinction, adolescents required more extinction trials than
adults.
As an active learning process, extinction is largely mediated by
the formation of a new memory that is in competition with existing
drug-paired associations (Quirk, 2006). Adolescent latency to ex-
tinguish suggests that nonrewarded new memories may not be
strong enough to drive motivation in adolescence. Interestingly,
anatomical differences in the PFC of adolescents are consistent
with this line of thinking. We have recently discovered that the D1
dopamine receptor is overexpressed on glutamatergic output neu-
rons in the PFC during adolescence, whereas the D1 receptor is
preferentially expressed on GABAergic interneurons before and
after the adolescent period (Brenhouse & Andersen, 2007). In the
PFC, D1 receptors on pyramidal projection neurons regulate the
“perceived” significance of stimuli by gating nucleus accumbens
(NAc) activation (Seamans & Yang, 2004). Greater D1 activation
on these projections is coupled with a heightened inhibition by
interneurons in adolescence (Tseng, Amin, Lewis, & O’Donnell,
2006). D1-mediated activation increases stimulus-driven PFC out-
put to the NAc only when stimuli are of sufficient potency to
overcome this hypofrontality (Kalivas et al., 2003). Adolescent
resistance to extinction may therefore involve the heightened D1
tone on PFC output neurons, allowing only potent stimuli (such as
cocaine-related cues) to overcome a high threshold for PFC output
and acquisition of motivational salience. Consequentially, during
this window of receptor distribution and overexpression (Andersen
et al., 2000), stimuli strongly associated with DA release (such as
cocaine exposure) may lock in a memory for associated contexts.
This impact of cortical DA on drug-cue associations is separable
from the amount of DA in downstream structures such as the
nucleus accumbens, which influences the direct reinforcing and
motor effects of cocaine and does not differ after cocaine exposure
between adolescents and adults (Frantz et al., 2007).
A priming injection of a drug after extinction renews the sig-
nificance or salience of the drug-related environmental stimuli,
driving the animal to seek the drug (Mueller & Stewart, 2000).
Reinstatement of extinguished drug-seeking with the learning par-
adigm of CPP (Mueller & Stewart, 2000) was used here to show
that adolescents display more robust drug-primed reinstatement of
CPP than adults. Magnitude of reinstatement, however, was not
found to correlate directly with either initial place preferences or
with the number of days required for extinction. This further
suggests that stronger initial associations are not sufficient to
explain the adolescent vulnerability to relapse after a drug chal-
lenge. The preferential salience attribution to potent stimuli dis-
cussed above may cause a cocaine exposure to reinstate adolescent
drug seeking to a greater extent than adults. It is also important to
note that stress-induced reinstatement is mediated through a dif-
ferent circuitry than drug-primed reinstatement (Kreibich &
Blendy, 2004; Sanchez et al., 2003), and therefore, developmental
differences in the vulnerability to stress-primed reinstatement still
needs to be investigated.
The present results suggest that adolescents may establish more
resilient associations between rewarding drug exposure and drug-
paired cues, and therefore show delayed extinction of drug seeking
compared to adults. Once extinguished, adolescents also displayed
reinstatement of memory for a lower dose of cocaine than adults
and showed a greater preference for a previously drug-paired
environment upon reinstatement. These findings suggest that, in
the behavioral paradigm examined here, memories for cocaine-
associated cues are particularly strong during this stage, likely
because of enhanced motivational salience for drug-paired events
at the expense of other information. This heightened salience
attribution during adolescence may require atypical strategies for
drug abuse intervention during the adolescent period, such as
extended treatment that involves substitution with different re-
wards, for example, exercise or music. The coincidence of cortical
remodeling (Brenhouse & Andersen, 2007), its role in associating
reward-related cues to consequences (Kalivas et al., 2005), and
drug exposure during adolescence may produce drug-linked asso-
ciations that are extremely difficult to change, reduce, or extin-
guish.
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Received August 20, 2007
Revision received October 10, 2007
Accepted October 12, 2007 䡲
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