Adolescent Vulnerabilities to Chronic Alcohol or
Nicotine Exposure: Findings From Rodent Models
Susan Barron, Aaron White, H. Scott Swartzwelder, Richard L. Bell, Zachary A. Rodd, Craig J. Slawecki, Cindy L. Ehlers,
Edward D. Levin, Amir H. Rezvani, and Linda P. Spear
This article presents an overview of the proceedings from a symposium entitled “Is adolescence special?
Possible age-related vulnerabilities to chronic alcohol or nicotine exposure,” organized by Susan Barron
and Linda Spear and held at the 2004 Research Society on Alcoholism Meeting in Vancouver, British
Columbia. This symposium, cosponsored by the Fetal Alcohol Syndrome Study Group and the Neurobe-
havioral Teratology Society, focused on our current knowledge regarding the long-term consequences of
ethanol and/or nicotine exposure during adolescence with the emphasis on data from rodent models. The
support from these two societies represents the understanding by these research groups that adolescence
represents a unique developmental stage for the effects of chronic drug exposure and also marks an age in
which many risky behaviors including alcohol consumption and smoking typically begin. The speakers
included (1) Aaron White, who presented data on the effects of adolescent ethanol exposure on subsequent
motor or cognitive response to an ethanol challenge in adulthood; (2) Richard Bell, who presented data
suggesting that genetic differences could play a role in adolescent vulnerability to ethanol; (3) Craig
Slawecki, who presented data looking at the effects of chronic exposure to alcohol or nicotine on neuro-
physiologic and behavioral end points; and (4) Ed Levin, who presented data on acute and long-term
consequences of adolescent nicotine exposure. Finally, Linda Spear provided some summary points and
recommendations regarding unresolved issues and future directions.
young as 11 to 12 and spanning the teenage years), al-
though some researchers expand their definition of adoles-
cence to include the early 20s as well. Adolescents are more
likely to experiment with a variety of unsafe behaviors,
including drug use (Martin et al., 2002). It has been shown
repeatedly that this is often a time for the first use of both
alcohol and tobacco (Grant et al., 1987; Kandel and
Yamaguchi 1985; Nelson et al., 1995; Webster et al., 1994).
Individuals who do not start using these drugs during ado-
DOLESCENCE IN HUMANS is typically defined as
spanning the second decade of life (i.e., starting as
lescence rarely initiate use in later life (Chen and Kandel,
1995; Kandel and Logan, 1984). The consequence of these
findings is that a considerable amount of research now
focuses on the adolescent, as we try to understand the
unique nature of this age group. Although numerous envi-
ronmental and peer-related explanations for this increase
in risky behaviors exist, we now have a better understanding
of some of the considerable pharmacologic and neuroana-
tomic changes occurring in the organism at this age (see
Spear, 2000 for review). For example, the dorsolateral pre-
frontal cortex, an area that has been implicated in impulse
control, continues to undergo considerable development
during adolescence (e.g., Giedd, 2004; Sowell et al., 2001).
Furthermore, there are marked changes in sensitivity to
pharmacologic challenges during adolescence that probably
contribute to the increased risk for adolescent drug use
(Chambers et al., 2003).
Because the adolescent brain continues to undergo con-
siderable growth and change, there is currently much con-
cern regarding the long-term consequences of drug expo-
sure during this critical period. Clinical studies are
beginning to suggest that there can be marked conse-
quences of chronic exposure during adolescence to a num-
ber of drugs, including ethanol (Grant et al., 1997), and,
more recently, nicotine (Jacobsen et al., 2005), but much
more work is needed in this area. Animal models have been
extremely useful and important in beginning to address
these questions. The papers discussed below present data
From the Psychology Department, University of Kentucky, Lexington, KY
(SB); Indiana University School of Medicine, Institute of Psychiatric Re-
search, Indianapolis, Indiana (RLB, ZAR); the Department of Psychiatry
and Behavioral Sciences, Duke University Medical Center, Durham, North
Carolina (AW, HSS, EDL, AHR); Scripps Research Institute, La Jolla,
California (CJS, CLE); and the Center for Developmental Psychobiology,
Department of Psychology, Binghamton University, Binghamton, New York
Received for publication May 2, 2005; accepted May 16, 2005.
Supported in part by grants AA12600 and AA14032 (to SB), AA10256 and
AA11261 (to RLB), AA12478 and VA Senior Research Career Scientist
Award (to HSS), AA00298 and AA014339 (to CJS), AA06059 (to CLE),
DA015756 and MH64494 (to EDL), and AA12150 and AA12525 (to LPS).
Reprint requests: Dr. Susan Barron, Kastle Hall, Lexington, KY, 40506-
0044; Fax: 606-323-1979; E-mail: email@example.com
Copyright © 2005 by the Research Society on Alcoholism.
ALCOHOLISM: CLINICAL AND EXPERIMENTAL RESEARCH
Vol. 29, No. 9
Alcohol Clin Exp Res, Vol 29, No 9, 2005: pp 1720–1725
from rodent models of chronic adolescent exposure to
either ethanol and/or nicotine. These well-established mod-
els provide critical data suggesting that adolescent rats
appear particularly sensitive to some of the potentially
long-term effects of such exposure.
ETHANOL EXPOSURE DURING ADOLESCENCE AFFECTS
VULNERABILITY TO ETHANOL-INDUCED IMPAIRMENTS
Aaron M. White and H. Scott Swartzwelder
Mounting evidence suggests that adolescents and adults
are differentially sensitive to many of the acute and chronic
effects of ethanol. When treated acutely, adolescent rats
are far less sensitive than adults to the impact of ethanol on
motor coordination. Adolescents are able to maintain their
balance at doses that produce significant impairments in
adults (White et al., 2002a).
In contrast to acute exposure, adolescents appear to be
more vulnerable than adults to the chronic effects of eth-
anol treatment on motor function (White et al., 2002b). In
adolescents but not adults, chronic exposure to ethanol
leads to changes in sensitivity to ethanol-induced motor
impairments that persist long after the last exposure to the
drug. Although saline-treated control subjects become
more sensitive to the motor-impairing effects of ethanol as
they progress from adolescence to adulthood, adolescents
treated with chronic-intermittent ethanol (CIE; 5.0 g/kg IP,
every 48 hours for 20 days) do not show the normal pattern
of increased sensitivity to ethanol as they age. In these
subjects, the impact of acute ethanol on motor coordina-
tion remains unchanged before, two days after, and 16 days
after completion of CIE treatment. In contrast, CIE treat-
ment during adulthood has little impact on the subsequent
effects of ethanol on motor coordination.
It appears that adolescents might also be more vulnerable
than adults to the long-lasting effects of ethanol exposure on
memory formation. White et al. (2000) observed that CIE
treatment during adolescence but not adulthood leads to a
long-lasting increase in vulnerability to ethanol-induced mem-
ory deficits. Adolescent and adult subjects were treated with
CIE as described above; then, after the treatment period was
completed, they were trained on a spatial working memory
task. All subjects acquired the task at similar rates. However,
when their memory was tested under acute ethanol (1.5 g/kg),
which occurred one full month after their last treatment in the
CIE regimen, subjects treated with CIE during adolescence
performed more poorly than the other groups. This finding is
consistent with a recent report on the impact of ethanol on
memory in college students. Weissenborn and Duka (2003)
assessed the impact of acute ethanol exposure on memory in
college students. Those with a history of binge-pattern drink-
ing performed more poorly while intoxicated than did other
Collectively, the above findings raise the possibility that
chronic ethanol exposure during adolescence could alter
the normal trajectory of brain development in long-lasting,
perhaps permanent, ways.
ETHANOL CONSUMPTION DURING ADOLESCENCE AND
ITS LONG-TERM CONSEQUENCES
Richard L. Bell and Zachary A. Rodd
Ethanol abuse continues to be a health concern for
today’s youth, necessitating the development of animal
models of adolescent ethanol abuse (Spear, 2000; Witt,
1994). Toward this end, our laboratory has studied the
acquisition of ethanol drinking behavior during adoles-
cence (PND 30 to 60) in selectively bred alcohol-preferring
(P) rats (Bell et al., 2003). Under 24-hour, free-choice
conditions, adolescent P rats readily self-administer 15%
ethanol attaining intakes of approximately 7.5 g/kg per day.
Additionally, concurrent access to multiple concentrations
of ethanol (10%, 20%, and 30%) further increases their
intake to approximately 10.0 g/kg per day (Bell et al., 2003).
Ethanol abuse during adolescence has been linked to
later abuse in adulthood. Early onset of alcohol use leads to
a higher risk for developing alcohol dependence in adult-
hood (Grant and Dawson, 1997), with age of first use
influencing the impact of other risk factors (e.g., parental
use, peer use and ethnicity: Hawkins et al., 1997). Given
this, our laboratory has examined the effect of adolescent
(PND 30 to 60) free-choice drinking of ethanol (15%) on
self-administration of ethanol under operant conditions
during adulthood (? PND 75; Rodd-Henricks et al.,
2002a). The operant paradigm consisted of taking the an-
imals through stages of acquisition, extinction, home-cage
rest, Pavlovian spontaneous recovery (testing for spontane-
ous responding on a lever previously paired with reinforce-
ment in the absence of reinforcement; c.f., Rodd et al.,
2004), home-cage rest, and the alcohol deprivation effect,
which is a transient increase in the consumption of ethanol
after a period of deprivation (Sinclair and Senter, 1967)
during reinstatement of access to ethanol. Compared with
naive P rats, P rats with access to ethanol during adoles-
cence displayed (a) quicker acquisition of operant self-
administration (first vs fourth day), (b) inhibited extinction,
with greater responding on the fourth through sixth days of
extinction, (c) greater responding on the 1st through 4th
days during testing for Pavlovian spontaneous recovery of
responding (considered ethanol-seeking behavior), and (d)
greater responding on the 2nd through 4th days during a
test for the alcohol deprivation effect, which is considered
relapse-like behavior (Rodd–Henricks et al., 2002a). Fur-
thermore, 30 consecutive days of ethanol (15%) access
during adulthood did not affect these parameters (Rodd–
Henricks et al., 2002b).
Ethanol, similar to other drugs of abuse, activates the
mesolimbic dopamine system (c.f., Koob et al., 1998a; Koob
et al., 1998b), with operant self-administration of ethanol
increasing extracellular levels of dopamine in the nucleus
accumbens (NAcc; e.g., Melendez et al., 2002; Weiss et al.,
ADOLESCENT VULNERABILITY TO ALCOHOL OR NICOTINE EXPOSURE
1993). Therefore, using microdialysis techniques, our lab-
oratory has examined whether free-choice access to ethanol
(15%) during adolescence (PND 30 to 60) would alter this
system during adulthood (PND ?75; Sahr et al., 2004).
Compared with naive P rats, P rats with adolescent access
to ethanol displayed a greater extraction fraction (a puta-
tive measure of dopamine reuptake) but not increased
extracellular levels of dopamine in the NAcc and displayed
a more prolonged increase in extracellular levels of dopa-
mine in the NAcc after a 2.5 g/kg challenge (IP) of ethanol
(Sahr et al., 2004).
Overall, these results suggest that individuals who are
genetically vulnerable to the development of alcoholism
may readily self-administer ethanol during adolescence and
that environmental manipulations can increase their intake.
Additionally, ethanol experience during adolescence, for
these individuals, may enhance the potential for initiating
ethanol drinking in adulthood, make it more difficult to
stop drinking once started, and increase the potential for
relapse during abstinence. Moreover, for these individuals,
ethanol experience during adolescence may have a signifi-
cant impact on neural systems implicated in mediating the
rewarding effects of ethanol.
CHRONIC ALCOHOL OR NICOTINE EFFECTS IN
ADOLESCENT RAT MODELS
Craig J. Slawecki and Cindy L. Ehlers
Adolescence is a time when binge alcohol consumption
and/or smoking is often initiated (Substance Abuse and
Mental Health Services Administration, 2004). In this pre-
sentation, studies examining the neurophysiologic, behav-
ioral, and neurochemical effects of alcohol or nicotine
exposure during adolescence were summarized and con-
trasted. Some of these data have been reported in detail
(Slawecki et al., 2001; Slawecki et al., 2003; Slawecki et al.,
2004; Slawecki and Ehlers, 2002).
In these studies, adolescent rats ranging from 30 to 45
days old were used. Alcohol exposure studies were con-
ducted by using 10 to 14 days of intermittent (12 hr/d; mean
blood alcohol level, 250 mg/dl) vapor inhalation. Nicotine
exposure studies used transdermal patches (Nicoderm CQ,
Smith-Kline Beecham, Pittsburgh, PA). The treatment reg-
imen consisted of five days of exposure to 5 mg/kg per day
nicotine (blood nicotine levels, ?50 to 80 ng/ml). After
drug abstinence periods ranging from three to nine weeks,
the neurobehavioral consequences of ethanol or nicotine
exposure were assessed. Neurophysiologic examinations
consisted of assessment of the electroencephalogram
(EEG) and auditory event–related potentials (Slawecki et
al., 2001). Behavioral assessments ranged from locomotor
activity assessment to behavior in the forced swim test and
In neurophysiologic assessments, ethanol exposure was
found to increase parietal cortical 1 to 2 Hz and hippocam-
pal 16 to 32 Hz peak frequency in the EEG. In contrast,
nicotine exposure resulted in decreased slow wave power in
the frontal cortical EEG. The effects of ethanol and nico-
tine exposure on event-related potentials were opposite,
with adolescent ethanol exposure decreasing cortical N1
amplitude and adolescent nicotine exposure increasing cor-
tical N1 amplitude. In each case, these changes were found
more than six weeks after the termination of drug exposure.
The protracted behavioral effects of ethanol and nicotine
exposure (i.e., after three to seven weeks) also differ. Eth-
anol exposure had no effect on motor activity but did
produce mild increases in depressive-like behavior in the
forced swim test. In contrast, nicotine exposure produced
hypoactivity and had antidepressant-like effects in the swim
test. The antidepressant-like effects of adolescent nicotine
exposure were particularly interesting in light of the pre-
liminary neurochemical analyses, which revealed increased
brain levels of hippocampal neuropeptide Y (NPY) after
adolescent nicotine exposure. Previous studies have dem-
onstrated that increased levels of hippocampal NPY are
associated with effective antidepressant treatments (Mathe ´
et al., 1998; Weiss et al., 1998). This could suggest that the
increased hippocampal NPY levels associated with adoles-
cent nicotine exposure is a neurochemical index of the
antidepressant effects of nicotine.
In summary, ethanol and nicotine exposure during adoles-
cence produce differing neurophysiologic, behavioral, and
neurochemical consequences. To date, alcohol exposure ap-
pears to be associated with a variety of long-term cognitive
deficits (i.e., perhaps deficits in attention and memory func-
tion). In contrast, adolescent nicotine exposure may produce
behavioral alterations that are more readily interpreted as
fitting an anxiogenic and antidepressant profile.
ADOLESCENT RATS SHOW DIFFERENTIAL EFFECTS OF
NICOTINE AND ALCOHOL RELATIVE TO ADULTS
Edward D. Levin and Amir H. Rezvani
Adolescence is a vulnerable period for the onset of
drug abuse. In particular, nicotine and alcohol are the
most common forms of drug abuse during adolescence.
Neurobehavioral effects of these drugs on the adolescent
brain may have unique effects, given that the brain is still
undergoing critical phases of late development during
adolescence. We have found in rat models that adoles-
cents can have a significantly differential response to
nicotine and alcohol relative to adults. Depending on the
neurobehavioral function, adolescents can be signifi-
cantly over-responsive or under-responsive to nicotine
and alcohol relative to adults. In other cases, no age-
related differences in response are seen. This pattern of
effects suggests selective vulnerabilities circumscribed
neurobehavioral systems during adolescence. Determin-
ing this pattern of differential drug effects in adolescents
can help in the characterization of the critical age-
related differences in neural processes relevant to drug
BARRON ET AL.
We have found that when nicotine self-administration
begins during adolescence, female rats self-administer
nearly twice the amount of nicotine per kilogram body
weight than adults (p ? 0.05) on the same reinforcement
schedule (Levin et al., 2003). This was seen over a broad
range of nicotine infusion doses and was persistent with
continued self-administration testing into adulthood.
In another experiment, we have demonstrated that ado-
lescent rats showed significantly (p ? 0.05) greater
nicotine-induced hypothermia than adult rats, and they
were also over-responsive to the hypothermia caused by a
combination of nicotine and ethanol (p ? 0.05) (Rezvani
and Levin, 2004). Chronic nicotine infusion during adoles-
cence caused a significant improvement in working memory
in a similar fashion as it does in adults. However, there was
a significant (p ? 0.05) initial learning impairment when
rats with a history of adolescent nicotine were trained as
adults. In addition, these adolescent nicotine-exposed rats
showed anomalous reactions to the nicotinic antagonist
In summary, adolescent rats show differential effects of
nicotine compared with adults with higher rates of nicotine
self-administration. Adolescent rats also show differential
responsivity to the hypothermic effects of nicotine and its
interaction with ethanol. Finally, persistent learning im-
pairments are seen after adolescent nicotine exposure de-
spite the fact that during the period of exposure, nicotine
improves cognitive performance. Adolescence is an impor-
tant period to study because the great majority of drug
abuse begins during this period when brain development is
ADOLESCENT VULNERABILITIES TO CHRONIC ALCOHOL
OR NICOTINE EXPOSURE: SUMMARY AND CONCLUDING
Linda Patia Spear
The presentations in this symposium have examined con-
sequences of chronic alcohol and nicotine exposure, with a
focus on adolescence. This age period is a time of particular
importance for assessing consequences of exposure to these
drugs, given that it is when most alcohol and nicotine use is
initiated, with signs of abuse and dependence emerging in
some human adolescents (Johnston et al., 2001). This early
use may be in part biological in that it is conserved across
species, with animal models of adolescence in rats likewise
revealing that adolescents often consume notably more
alcohol (Doremus et al., 2005) and find nicotine more
rewarding (Vastola et al., 2002) than do adults.
Research using animal models of adolescence has sup-
ported the suggestion that the predisposition of adolescents
for alcohol and nicotine use may be related in part to an
attenuated sensitivity to certain aversive effects of these
substances. For instance, young rats through adolescence
are markedly less sensitive than adults to the sedative
(Silveri and Spear, 1998) and motor impairing (Silveri and
Spear, 2001) effects of ethanol and to the activity-
suppressing effects of nicotine (Vastola et al., 2002). Like-
wise, adolescents are less sensitive than adults to certain
unpleasant consequences associated with withdrawal from
these compounds, including under some circumstances the
anxiogenesis seen during the withdrawal period after
chronic nicotine exposure (Wilmouth, 2004) or during the
“hangover” after exposure to a large amount of ethanol
(Doremus et al., 2003; also see Doremus, 2004, for excep-
tions to this generality). These adolescent-associated atten-
uations in ethanol responsiveness appear in part attribut-
able to age-related neural alterations (Silveri and Spear,
2002) as well as to ontogenetic differences in acute toler-
ance (Silveri and Spear, 2004) and to pharmacokinetic
factors (see Spear and Varlinskaya, 2005, for review and
references). Attenuated responsiveness to adverse ethanol
effects normally serving as cues to moderate intake may
support elevated consumption levels during adolescence
and may be of relevance for the ontogeny of alcohol use
disorders, given evidence for low responsiveness to ethanol
as a risk factor for alcoholism (Schuckit et al., 2004). In-
deed, adolescence may be a time of confluence of a number
of contributors to low ethanol responsiveness in vulnerable
adolescents, with the genetic insensitivities of individuals
with a family history of alcohol abuse potentially combining
with age-typical ethanol insensitivities and possible further
attenuations in alcohol responsiveness associated with nic-
An adolescent insensitivity to certain acute effects of
these drugs does not mean that adolescents are protected
from long-term adverse consequences after chronic adoles-
cent exposure to nicotine and/or ethanol. Indeed, as de-
tailed in other presentations in this symposium, exposure to
either or both of these drugs at the time of the rapid brain
changes associated with adolescence may produce lasting
consequences that are age-specific, drug-specific, and with
interactive effects when both drugs are combined. Re-
search in the area of chronic adolescent drug exposure is
challenging in several respects. For instance, when using
animal studies to model adolescent drug use and to deter-
mine age specificity of resulting long-term consequences, it
is critical to consider whether patterns of drug exposure are
relevant to those of human use and are equated across age.
Administering the same g (or mg)/kg drug dose across age
may not equate profiles of drug exposure if there are
age-related differences in pharmacokinetics or drug distri-
bution patterns. When comparing efficacy of single versus
combined exposure of two drugs across age, additional
challenges include choosing across-drug dose equivalen-
cies, determining dependent measures appropriate for as-
sessing effects of each drug alone and in combination, and
designing and analyzing the data in ways that permit de-
tection of additive, multiplicative, or protective effects,
should they exist. As is always the case when comparing
lasting consequences of drug exposures at different points
during the lifespan, there is the challenge of choosing
ADOLESCENT VULNERABILITY TO ALCOHOL OR NICOTINE EXPOSURE
assessment times and the quandary that testing animals at
the same postdrug recovery interval confounds test age
across groups, whereas assessing animals at the same post-
natal age regardless of the timing of drug exposure con-
founds length of postdrug recovery. These and other chal-
lenges for research in this area are being addressed in
creative and thoughtful ways, as illustrated by the presen-
tations in this symposium. Using lessons learned in part
from developmental toxicologic studies of chronic drug
exposure early in ontogeny, research in the critical emerg-
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ADOLESCENT VULNERABILITY TO ALCOHOL OR NICOTINE EXPOSURE