Pharmacology, Biochemistry and Behavior 101 (2012) 458–464
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Pharmacology, Biochemistry and Behavior
journal homepage: www.elsevier.com/locate/pharmbiochembeh
Ethanol exposure during either adolescence or adulthood alters the rewarding effects
of cocaine in adult rats
Mary Anne Hutchison ⁎, Anthony L. Riley
Psychopharmacology Laboratory, Department of Psychology, American University, Washington, DC 20016, USA
a r t i c l e
i n f o
Article history:
Received 16 September 2011
Received in revised form 6 February 2012
Accepted 8 February 2012
Available online 15 February 2012
Keywords:
Adolescence
Alcohol
Ethanol
Cocaine
Conditioned place preference
Rat
a b s t r a c t
Objectives: The present studies assessed the effects of adolescent and adult ethanol exposure on the rewarding effects of cocaine as measured with the conditioned place preference procedure.
Methods: Male rats were exposed to intraperitoneal (IP) injections of ethanol or vehicle for 10 days [postnatal
days (PNDs) 30–39 or PNDs 70–79; 2 mg/kg]. Place preference conditioning began on PND 65 or PND 105,
respectively, and consisted of a baseline test followed by four conditioning cycles with either 0, 5, 10 or
20 mg/kg cocaine. Following the fourth conditioning cycle a final preference test was performed. Changes
in time on the drug-paired side between the baseline and final test were analyzed.
Results: Animals exposed to vehicle (during adolescence or adulthood) showed a significant place preference
at 20 mg/kg cocaine. Animals exposed to ethanol (during adolescence or adulthood) showed a significant
place preference at 10 mg/kg cocaine.
Conclusions: Exposure to ethanol (adolescents or adults) sensitized the rewarding effects of cocaine. This may
indicate an increase in the abuse liability of cocaine following a history of ethanol exposure.
© 2012 Elsevier Inc. All rights reserved.
1. Introduction
Alcohol is the most commonly used drug during adolescence, e.g.,
in 2010 65.2% of twelfth graders reported using alcohol in the past
year (Johnston et al., 2011). In addition to being widely used by adolescents, early alcohol use is correlated with an increased likelihood
to abuse alcohol and other drugs later in life (Cable and Sacker,
2008; Duncan et al., 1997; Grant and Dawson, 1997; Yu and
Williford, 1992). Animal models of adolescent ethanol exposure
have supported this human research by showing that early experience with ethanol alters the subsequent response to ethanol. For example, adolescent exposure to ethanol has been shown to produce
tolerance to a number of ethanol-induced behavioral impairments
in adulthood (see Matthews et al., 2008; Pascual et al., 2007;
Slawecki, 2002; White et al., 2002). In addition to altering the intoxicating effects of ethanol, early exposure also alters the motivational
properties of ethanol in adulthood. In one series of studies, researchers showed that exposure to ethanol vapor during adolescence
subsequently attenuated ethanol-induced taste aversions (DiazGranados and Graham, 2007; Graham and Diaz-Granados, 2006). Interestingly, this effect was not seen when the initial exposure to ethanol occurred during adulthood (Diaz-Granados and Graham, 2007).
⁎ Corresponding author at: Psychopharmacology Laboratory, Department of Psychology, American University, 4400 Massachusetts Avenue, NW, Washington, DC
20016, USA. Tel.: + 1 202 885 1731; fax: + 1 202 885 1081.
E-mail addresses: hutchison.ma@gmail.com (M.A. Hutchison),
alriley@american.edu (A.L. Riley).
0091-3057/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.pbb.2012.02.007
Exposure to ethanol early in life also alters the rewarding effects of
ethanol in adult rats. In one study, animals with a history of ethanol
consumption during adolescence showed increased responding,
slower extinction and enhanced reacquisition in an ethanol selfadministration preparation (Rodd-Henricks et al., 2002). Similarly,
other studies have found that early exposure to ethanol leads to increased ethanol consumption in adult rats (Pascual et al., 2009;
Sherrill et al., 2011; Siciliano and Smith, 2001), although in one
study this effect was only seen in female subjects (Sherrill et al.,
2011).
Although work with animal models has shown that early ethanol
exposure alters the response to ethanol administered later in life, surprisingly little work has been done to examine how such an ethanol
history may subsequently impact the response to other drugs. Recent
work has shown that exposure to ethanol during adolescence attenuates the aversive effects of cocaine (Hutchison et al., 2010) in adult
rats. However, no work has been done to examine how early ethanol
exposure may subsequently impact the rewarding effects of other
drugs. In humans, adolescent alcohol use precedes the use of other
drugs such as cocaine (Degenhardt et al., 2010; Kandel et al., 1992)
and can be seen as a predictor for drug-related problems in adulthood
(Johnson et al., 2000; Kandel et al., 1992; Yu and Williford, 1992).
Given that in 2009, approximately 21.8 million Americans aged 12
or older reported using illicit drugs in the last month (Substance
Abuse and Mental Health Services Administration, 2010), it is important to examine how adolescent exposure to alcohol may influence
the abuse liability of other drugs. Therefore, the present study examined the effect of adolescent ethanol exposure on the rewarding
M.A. Hutchison, A.L. Riley / Pharmacology, Biochemistry and Behavior 101 (2012) 458–464
properties of cocaine in adulthood. This was assessed using the conditioned place preference (CPP) design (see Bardo and Bevins, 2000;
Sanchis-Segura and Spanagel, 2006; Tzschentke, 1998, 2007). To determine if any potential effects were age-related, ethanol was given
during both the adolescent (Experiment 1) and adult (Experiment
2) developmental periods.
459
the effects of ethanol exposure on cocaine responsivity (Grakalic and
Riley, 2002; Hutchison et al., 2010; Slawecki and Betancourt, 2002;
Slawecki et al., 2001). Group assignments were made such that animals in each bin (see above) were administered the same compound.
Injections were given daily for 10 consecutive days (PNDs 30–39).
From PND 40 to PND 54, subjects were maintained in their home
bins until place conditioning (see below).
2. Experiment 1: adolescent ethanol exposure
2.1.5. Place preference conditioning
2.1. Procedure
2.1.1. Subjects
Subjects (n = 67) were experimentally naïve male Sprague Dawley rats (Harlan Sprague Dawley Laboratories). The experiment was
run in two replicates (n = 35 in the first replicate, n = 32 in the second) under identical parameters, and data were pooled for analysis.
All groups were represented in each replicate. Animals arrived in
the laboratory on postnatal day (PND) 25 and were housed in Plexiglas bins (26 × 48 × 21 cm) with three or four animals in each bin in
a colony room maintained on a 12-h light/dark cycle (lights on at
0800 h) and at an ambient temperature of 23 °C. Training and testing
took place during the light part of the cycle, with all procedures beginning at 1200 h. Food and water were available ad libitum for the
entirety of the study. Animals were handled daily for 5 days prior to
the start of the experiment to limit the effects of handling stress during the conduct of the research. Procedures recommended by the
Guide for the Care and Use of Laboratory Animals (National
Research Council, 1996), the Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (National Research
Council, 2003) and the Institutional Animal Care and Use Committee
at American University were followed at all times. Food and water
consumption and body weight were monitored daily to assess the
health of the subjects.
2.1.2. Drugs and solutions
Ethanol (Sigma Aldrich Co., St. Louis, MO) was prepared as a 15%
(v/v) solution in 0.9% saline. Cocaine hydrochloride (generously supplied by NIDA) was prepared as a 10 mg/ml solution in 0.9% saline.
Doses of cocaine refer to the weight of the salt. Saline was used for vehicle injections.
2.1.3. Apparatus
All place conditioning procedures were conducted using a 3chambered automated apparatus (San Diego Instruments Place Preference system, San Diego, CA). The inner dimensions of each main
conditioning chamber were 28 cm wide × 21 cm deep × 34.5 cm
high; the two chambers were adjoined by a smaller middle chamber
measuring 14 cm wide × 21 cm deep × 34.5 cm high. One of the main
conditioning chambers featured a white aluminum diamond plate
floor with white walls, the other conditioning chamber featured a
haircell textured black plastic floor with black walls and the smaller
middle chamber was outfitted with a steel rod floor and gray walls.
Each individual chamber within each apparatus had two white LED
lights set to minimal brightness within the otherwise unlit room. A
total of eight identical apparatuses were used; each apparatus featured a 16 × 4 photobeam array for recording time (sec) spent in
each chamber. The room in which the apparatuses were located was
illuminated by an 85-watt red light mounted to the ceiling in the center of the room, and background noised was masked by a white noise
generator located in the front of the room.
2.1.4. Ethanol preexposure
On PND 30, animals were divided into two groups and injected intraperitoneally (IP) with either ethanol (Group E; 2.0 g/kg; n = 35) or
vehicle (Group V; n = 32). The time course, dose and route of administration of ethanol were chosen to match previous studies examining
2.1.5.1. Baseline test. On PND 55, animals were individually housed in
hanging wire cages (24.3 × 19 × 18 cm) and allowed 10 days to acclimate to this environment. This procedure was chosen to match previous work assessing the interaction of alcohol and cocaine (see Busse
et al., 2004, 2005; Busse and Riley, 2002; Diaz-Granados and Graham,
2007; Graham and Diaz-Granados, 2006). On PND 65, baseline chamber preferences were determined by placing each animal in the center
compartment of the CPP apparatus, then removing the barriers and
allowing it free access to the entire apparatus for 15 min. A pairedsamples t-test revealed that animals spent significantly less time in
the white chamber than the black chamber (268 versus 354 s, t(66) =
−5.1, p b 0.001), indicating a significant apparatus bias (Cunningham
et al., 2003; Roma and Riley, 2005); there were no differences between
preexposure groups in time spent in either the black or white chambers
(ps > .05). Given that the animals showed an initial side preference in
the apparatus, a biased conditioning design was used such that all subjects received drug in the white (least-preferred) chamber (see also
Kelley and Rowan, 2004; Schramm-Sapyta et al., 2004).
2.1.5.2. Acquisition and final test. The CPP acquisition phase began on
PND 66. Subjects in each of the two preexposure conditions, i.e.,
Groups V and E, were randomly assigned a conditioning dose of cocaine (5, 10 or 20 mg/kg) or vehicle (matched in volume to the
20 mg/kg dose of cocaine). This treatment resulted in eight groups
designated as follows: V0 (n = 8), V5 (n = 8), V10 (n = 8), V20
(n = 8), E0 (n = 8), E5 (n = 9), E10 (n = 9) and E20 (n = 9). The first
letter stands for the preexposure condition (ethanol or vehicle), and
the second letter or number stands for the conditioning injection (vehicle or 5, 10 or 20 mg/kg cocaine). On Day 1 of the conditioning
cycle, half of the animals were administered their conditioning injection (vehicle, 5, 10 or 20 mg/kg cocaine; IP) and confined to the white
chamber for 30 min. The remaining animals received a saline injection and were confined to the black chamber for 30 min. On Day 2,
animals experienced injections and chamber confinement opposite
to those of Day 1. All groups were counterbalanced across conditioning days. This 2-day sequence constituted one conditioning cycle, and
the acquisition phase consisted of four such cycles culminating in a
final CPP test on PND 74. During the final CPP test, animals were
placed in the center compartment and then allowed access to the entire apparatus for 15 min.
2.1.6. Data analysis
To assess health of the subjects, body weights were analyzed during ethanol preexposure and place preference conditioning. For both
the preexposure and conditioning phases, body weights were analyzed using repeated-measures ANOVAs. To assess the effects of ethanol preexposure on place preference conditioning, a 2 × 2 × 4
repeated-measures ANOVA with the within-subjects factor of Trial
(baseline or final CPP test) and the between-group factors of
Preexposure (vehicle or ethanol) and Dose (0, 5, 10 or 20 mg/kg
cocaine) was performed with seconds spent in the drug-paired
(white) chamber as the dependent variable. Following significant
main effects, differences between time spent in the drug-paired
chamber during baseline and final CPP tests were analyzed with
one-way ANOVAs followed by Tukey's post-hoc tests. To specifically
examine changes in preference for the white (drug-paired) chamber
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between the baseline and final CPP tests for each group, pairedsamples t-tests were used. Statistical significance was set at α = .05
for all analyses.
2.2. Results
2.2.1. Body weights
The 2 (Preexposure) × 10 (Day) repeated-measures ANOVA on body
weight during the preexposure phase revealed significant effects of
both Day [F(9, 585) = 2894.6; p b 0.001] and Preexposure [F(1, 65) =
14492.8; p b 0.001] as well as a significant Day × Preexposure interaction [F(9, 585)= 67.0; p b 0.05]. Independent-samples t-tests on each
day showed that on Days 4, 6, 7 and 8 animals that received ethanol injections weighed less than those that received saline during preexposure. Average body weights across these sessions were 0.141 kg for
Group V and 0.130 kg for Group E. The 2 (Preexposure) × 4
(Dose) × 10 (Day) repeated-measures ANOVA on body weights during
conditioning (including the baseline and final test session) revealed a
significant effect of Preexposure, with no other factors reaching significance. When body weights were averaged across conditioning sessions,
an independent-samples t-test revealed that the ethanol-preexposed
animals weighed significantly less than the animals that received vehicle during adolescence (p b 0.001). Average weights during the conditioning sessions were 0.340 kg for vehicle-preexposed animals and
0.317 kg for ethanol-preexposed animals.
2.2.2. Place preference conditioning
The 2 (Trial) × 2 (Preexposure) × 4 (Dose) repeated-measures
ANOVA on time in the drug-paired chamber revealed significant effects of Trial [F(1,59) = 9.892, p b .01], Preexposure [F(1,59) = 5.100,
p b .05] and Dose [F(3,59) = 5.388, p b .01], as well as significant Preexposure × Dose [F(3, 59) = 4.452, p b .01] and Trial × Preexposure ×
Dose [F(3,59) = 3.605, p b .05] interactions. Given the significant interaction of all three factors, further analyses were conducted to identify specific dose–response relationships within each preexposure
condition on the baseline and final CPP test.
One-way ANOVAs on time in the drug-paired chamber followed
by Tukey's post-hoc tests were performed on each trial (baseline
and final CPP test) to determine if there were any differences in
time spent on the white (drug-paired) side between groups. Analysis
of the baseline test (Fig. 1A) revealed significant differences between
groups (p b .05). Specifically, Group V-10 spent significantly more
time in the white chamber on this day than Group V-5. There were
no other significant differences between groups on this trial. During
the final CPP test (Fig. 1B), additional significant group differences
within each preexposure condition emerged. For the vehiclepreexposed animals, the group exposed to the highest dose of cocaine
(Group V-20) spent significantly more time in the drug-paired chamber than any of the other groups (ps b .05). For animals exposed to
ethanol during adolescence, subjects conditioned with 10 mg/kg cocaine spent significantly more time in the drug-paired chamber
than their controls (Group E-0; p b .05). None of the other groups (vehicle- or ethanol-preexposed) differed from controls. In addition,
there were no significant dose-dependent preexposure differences
on either trial.
To more specifically assess the development of a preference for
the drug-paired chamber, times spent in this compartment during
the baseline and final CPP tests were compared using pairedsamples t-tests for each group. A significant increase in time spent
in the drug-paired chamber during the final test would indicate a significant preference for that compartment. For animals preexposed to
saline (Fig. 2A), Group V-20 showed a significant increase in time
spent on the drug-paired chamber from baseline to the final test
(p b 0.01). No other vehicle-preexposed subjects showed a significant
increase in time in the drug-paired chamber. In subjects preexposed
to ethanol during adolescence (Fig. 2B), a significant increase in
Fig. 1. Experiment 1: Time spent in white chamber (+SEM) during (A) baseline and
(B) final CPP test by dose. * indicates significant difference between groups.
time spent in the drug-paired chamber was seen for the intermediate
dose, Group E-10 (p b 0.01). None of the other ethanol-exposed
groups showed a change in time spent in the drug-paired chamber
over trials.
3. Experiment 2: adult ethanol exposure
3.1. Procedure
The procedures used for the assessment of the effects of ethanol exposure in adults were identical to those described for the
adolescent subjects with the following exceptions. As in Experiment 1, Experiment 2 was run in two replicates (n = 32 in the
first replicate, n = 35 in the second) under identical parameters
and data was pooled for analysis. On PND 70, animals were divided into two groups and injected IP with either ethanol (Group E;
2.0 g/kg; n = 35) or vehicle (Group V; n = 32). Injections were
given daily for 10 consecutive days (PNDs 70–79). From PND 80
to PND 84, subjects were maintained in their home bins until
place conditioning (see below). On PND 85, animals were individually housed in hanging wire cages (24.3 × 19 × 18 cm) and
allowed 10 days to acclimate to this environment. For Experiment
2, the baseline preference test took place on PND 105. Similar to
Experiment 1, animals showed a significant preference for the
black relative to the white side of the chamber during the baseline
test (375 versus 283 s, paired-samples t(66) = − 5.7; p b 0.001),
with no differences between preexposure groups for time spent
in either the black or white chambers (ps > 0.05). Conditioning
began on PND 106, and the final CPP test took place following
four conditioning cycles (as above).
M.A. Hutchison, A.L. Riley / Pharmacology, Biochemistry and Behavior 101 (2012) 458–464
461
Fig. 3. Experiment 2: Time spent in white chamber (+SEM) during baseline and final
CPP test by dose. There were no significant differences between groups.
Fig. 2. Experiment 1: Time spent in white chamber (+SEM) during baseline and final
CPP test. (A) Subjects exposed to vehicle during adolescence; (B) subjects exposed to
ethanol during adolescence. * indicates significant difference between baseline and
final CPP tests for Groups V-20 and E-10.
3.2. Results
3.2.1. Body weight
The 2 (Preexposure) × 10 (Day) repeated-measures ANOVA on body
weight during the preexposure phase revealed a significant effect of
Day [F(9, 585) = 73.9; p b 0.001] and a significant Preexposure × Day interaction [F(9, 585) = 68.7; p b 0.001]. Independent-samples t-tests on
each day revealed that on Days 8–10 animals receiving ethanol injections weighed significantly less than those receiving vehicle injections
(ps b .05). Average weights across these 3 days were 0.354 kg for
Group V and 0.340 kg for Group E. The 2 (Preexposure) × 4
(Dose) × 10 (Day) repeated-measures ANOVA during conditioning
revealed a significant effect of Day [F(9, 531) = 24.207; p b 0.001], as
well as significant Preexposure × Day [F(9, 531)= 2.0; p b 0.05] and Preexposure × Dose× Day [F(27, 531)= 1.7; p b 0.05] interactions. However, one-way ANOVAs on each conditioning day did not reveal any
additional significant differences between groups (ps > 0.05).
3.2.2. Place preference conditioning
The 2 (Trial) × 2 (Preexposure) × 4 (Dose) repeated-measures
ANOVA revealed a significant effect of Trial [F(1, 59) = 10.335,
p b .01] as well as a Trial × Dose interaction [F(3, 59) = 6.558,
p b .001]. None of the terms involving Preexposure reached significance. To explore the main effect of Trial, a paired-samples t-test
revealed that time in the white chamber significantly increased between the baseline and final CPP tests (p b .01). The Trial × Dose
interaction was analyzed with one-way ANOVAs followed by Tukey's
post-hoc tests on each trial. During the baseline test (Fig. 3A), there
was an effect revealed by the one-way ANOVA [F(3, 66) = 2.819,
p b .05]. However, Tukey's post-hoc tests did not reveal any significant
differences between groups on this trial (ps > .05). Analysis on the
final CPP test (Fig. 3B) also revealed a significant difference between
doses [F(3, 66) = 4.109, p = .01]. Post-hoc analysis showed that
groups conditioned with 10 and 20 mg/kg cocaine spent significantly
more time in the white chamber than the saline-conditioned controls
(ps b .05).
To examine the specific changes in time spent in the drug-paired
chamber for each group, paired-samples t-tests were used to assess
differences in time spent in the drug-paired chamber between the
pretest and final CPP test. Group V-20 (Fig. 4A) and Group E-10
(Fig. 4B) showed a significant increase in time spent in the drugpaired chambers across trials (ps b 0.05). There were no significant
differences for any of the other groups.
4. Discussion
Experiment 1 was designed to assess the effects of ethanol exposure during adolescence on the rewarding effects of cocaine administered later in life. As described, a history of ethanol exposure
produced a leftward shift of the cocaine dose–response curve. Specifically, animals preexposed to saline and conditioned with
20 mg/kg cocaine increased the time spent in the drug-paired
chamber from baseline to the final test and spent more time in
the drug-paired chamber following conditioning. These same effects were evident in the ethanol-preexposed subjects when conditioned at 10 mg/kg cocaine. In a similar assessment in adults,
Experiment 2 found that animals preexposed to saline and conditioned with 20 mg/kg cocaine increased the time spent in the
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Fig. 4. Experiment 2: Time spent in white chamber (+SEM) during baseline and final
CPP test. (A) Subjects exposed to vehicle during adulthood; (B) subjects exposed to
ethanol during adulthood. * indicates significant difference between baseline and
final CPP tests for Groups V-20 and E-10.
drug-paired chamber from baseline to the final test while animals
exposed to ethanol displayed this increase at 10 mg/kg cocaine.
However, there was no effect of ethanol preexposure in adults
when the more conservative measure of time in the drug-paired
chamber was assessed. These results suggest that ethanol preexposure during both adolescence and adulthood sensitizes the rewarding effects of cocaine, although these sensitizing effects may be
weaker with adult exposure.
Adolescent exposure to ethanol has been shown to produce a wide
range of behavioral effects lasting into adulthood, including the production of lasting effects on drug-taking behaviors (Diaz-Granados
and Graham, 2007; Duncan et al., 1997; Graham and Diaz-Granados,
2006; Hutchison et al., 2010; Matthews et al., 2008; Pascual et al.,
2007; Pascual et al., 2009; Rodd-Henricks et al., 2002; Siciliano and
Smith, 2001; Slawecki, 2002; White et al., 2002). Interestingly, little
work has been done to examine how early exposure to ethanol may
impact the response to other drugs of abuse in adulthood. One such
study examined the effect of adolescent ethanol exposure on
cocaine-induced taste aversions in adult rats (Hutchison et al.,
2010). In this study, ethanol exposure during adolescence resulted
in an attenuation of cocaine-induced taste aversions in adult rats
(Hutchison et al., 2010). Given that the abuse liability of a drug can
be seen as a balance between its rewarding and aversive effects
(Brockwell et al., 1991; Simpson and Riley, 2005; Wise et al., 1976),
if a history of ethanol use attenuates the aversive effects of cocaine
(Hutchison et al., 2010) while sensitizing the rewarding effects as
seen in the present study, it would indicate an increase in the likelihood of cocaine abuse after ethanol exposure early in life. Such an effect would be consistent with the trends seen in human drug use,
where alcohol use precedes the use of drugs such as cocaine
(Degenhardt et al., 2010; Haertzen et al., 1983) and heavy use of alcohol in adolescence can be seen as a predictive factor for later drug
abuse (Cable and Sacker, 2008; Duncan et al., 1997; Grant and
Dawson, 1997; Yu and Williford, 1992).
The interaction between a history of ethanol exposure and subsequent cocaine-induced place preferences in adult rats has been explored in previous studies (Busse et al., 2005; Le Pen et al., 1998).
Interestingly, in those reports adult ethanol exposure did not produce
a sensitization to the rewarding effects of cocaine. Differences between the results reported here (Experiment 2) and this prior work
may be due to a number of parametric variations. In terms of the ethanol preexposure procedure, one of the previous studies (Busse et al.,
2005) used a series of five spaced injections of 1.5 g/kg ethanol, while
the other study (Le Pen et al., 1998) administered ethanol over
14 days in a free-drinking preparation. In contrast, adult animals in
Experiment 2 were exposed to 10 consecutive days of 2 g/kg ethanol
injections. It should be noted that this preexposure procedure was
chosen to match that of Experiment 1, which aimed to mimic ethanol
exposure across the course of the adolescent developmental period.
Given that adolescents tend to have higher levels of alcohol consumption than older adults (Substance Abuse and Mental Health Services
Administration, 2010), it may be that the adolescent exposure procedure employed in the present series of experiments caused sensitization in the animals exposed as adults that would not be seen with a
spaced preexposure regiment. One additional parameter that varied
between prior work and Experiment 2 was the conditioning dose of
cocaine. The present study used a dose–response approach to the
place conditioning procedure and found a preexposure effect at the
intermediate (10 mg/kg) dose of cocaine. In contrast, the previous
studies each only used one dose of cocaine, which may not have
detected all potential changes in the sensitivity to cocaine. Differences in these parameters may have resulted in the different results
found between the present work with adult exposure and earlier
work on ethanol's effects on conditioned place preferences in adult
rats.
The fact that cocaine-induced place preferences were evident at
lower doses in the ethanol-preexposed animals (when given during
adolescence and adulthood) can be explained by a shift in the sensitivity to the rewarding effects of ethanol. An interesting feature of
the current work, however, is that in both Experiments 1 and 2,
ethanol-preexposed animals no longer displayed preferences at the
20 mg/kg dose of cocaine (whereas vehicle-exposed controls did).
It is not clear why preferences were no longer evident at the higher
dose in the ethanol-preexposed subjects. In studies using animals
without a history of ethanol preexposure, place preferences have
also been seen with 20 mg/kg cocaine (Busse et al., 2004; Durazzo
et al., 1994). When ethanol and cocaine are given in combination
during place preference conditioning, an attenuated preference is
seen relative to subjects receiving cocaine alone (Busse et al.,
2004; Busse and Riley, 2002), suggestive of the possibility that ethanol enhanced cocaine's aversive effects. In the present study a
similar effect may have occurred, with the ethanol preexposure
history enhancing the aversive effects of the highest dose of cocaine. Alternatively, given that animals in both experiments of the
present manuscript were individually housed during CPP conditioning (see Busse et al., 2004, 2005; Busse and Riley, 2002; DiazGranados and Graham, 2007; Graham and Diaz-Granados, 2006;
Hutchison et al., 2010), isolation stress may have affected place
preference conditioning, interacting with cocaine to affect its aversive/rewarding properties at the higher dose in the ethanolpreexposed subjects (though see Gehrke et al., 2006; Smith et al.,
2009; Solinas et al., 2008).
M.A. Hutchison, A.L. Riley / Pharmacology, Biochemistry and Behavior 101 (2012) 458–464
As noted, in comparison to adolescent ethanol exposure, similar but
weaker results were seen when the preexposure was given during
adulthood. Both adolescent (Experiment 1) and adult (Experiment 2)
ethanol exposure produced an increased sensitivity to an intermediate
(10 mg/kg) dose of cocaine as measured by a significant change in
time spent in the drug-paired chamber between the baseline and final
tests. The change in sensitivity was also seen in Experiment 1 when
measured as time spent in the drug-paired chamber relative to controls
during the final test; however, in Experiment 2, no preexposure effects
were seen with this measure of place conditioning. Several previous
studies have found long-lasting effects of ethanol following adolescent,
but not adult, exposure (Bergstrom et al., 2006; Diaz-Granados and
Graham, 2007; Graham and Diaz-Granados, 2006; Sircar and Sircar,
2005; White et al., 2000). However, other studies examining the
long-term effects of adolescent and adult exposure to ethanol
(Hutchison et al., 2010; Silveri and Spear, 2001) as well as similar exposure to other drugs such as cocaine (Schramm-Sapyta et al., 2004)
have found no differences between age groups. These contrasting results across studies may indicate that differences between the longterm effects of adolescent and adult ethanol exposure might be dependent on the measures being tested. In addition to differences in
place preference conditioning, age-related differences were also
seen for ethanol's effect on body weights. Ethanol-induced decreases
in body weight were seen in the preexposure phase for both age
groups. In Experiment 1, these effects persisted through the conditioning phase, with all ethanol-preexposed groups showing a decrease in average body weight later in life. In contrast, in
Experiment 2, the body weight differences during the conditioning
phase were dependent on conditioning dose and trial as well as preexposure condition, and no differences between individual groups
reached significance. These results indicate that while ethanol preexposure effects may be seen following exposure during either adolescence or adulthood, exposure earlier in development may lead to
stronger long-term physical and behavioral changes. Given that alcohol use is most commonly initiated during adolescence (Degenhardt
et al., 2010; Johnston et al., 2011; Kandel et al., 1992; Substance
Abuse and Mental Health Services Administration, 2010), adolescence should be viewed as a critical developmental period that may
be involved in the later likelihood of drug misuse and abuse.
Because the rewarding effects of a drug play a strong role in its
abuse potential (Bardo and Bevins, 2000), a sensitization of the rewarding effects of cocaine following adolescent ethanol exposure
may indicate an increased likelihood of later cocaine abuse. To further clarify the role of ethanol in mediating cocaine's abuse liability,
it would be of interest to examine neural changes resulting from ethanol exposure early in life and how these changes may impact the biological response to cocaine. In addition, since adolescent ethanol
exposure alters both the rewarding (as shown in the present
study) and aversive (Hutchison et al., 2010) effects of cocaine, it
would also be of interest to see how such exposure may alter cocaine
self-administration. Since the rewarding and aversive effects of a
drug play a role in its abuse liability (Brockwell et al., 1991;
Simpson and Riley, 2005; Wise et al., 1976), the use of a selfadministration procedure would help to clarify how these effects
may translate to a model that more closely mimics human drugtaking behaviors. If early ethanol exposure reduces the aversive effect of cocaine (Hutchison et al., 2010) and also sensitizes its rewarding effects, it would be expected that adolescent ethanol exposure
would increase cocaine self-administration later in life. This would
parallel the drug-taking patterns seen in humans (Cable and
Sacker, 2008; Degenhardt et al., 2010; Duncan et al., 1997; Grant
and Dawson, 1997; Haertzen et al., 1983; Yu and Williford, 1992).
A full understanding of how early ethanol exposure alters the response to cocaine on both the biological and behavioral level would
be a large step towards understanding and potentially preventing
such patterns seen in human drug abuse.
463
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