0145-6008/05/2909-1720$03.00/0 ALCOHOLISM: CLINICAL AND EXPERIMENTAL RESEARCH
Vol. 29, No. 9 September 2005
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 Neurobehavioral 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 neurophysiologic 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.
INTRODUCTION
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DOLESCENCE IN HUMANS is typically defined as spanning the second decade of life (i.e., starting as young as 11 to 12 and spanning the teenage years), although some researchers expand their definition of adolescence 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 adoFrom the Psychology Department, University of Kentucky, Lexington, KY (SB); Indiana University School of Medicine, Institute of Psychiatric Research, 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 (LPS). 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, 405060044; Fax: 606-323-1979; E-mail:
[email protected] Copyright © 2005 by the Research Society on Alcoholism. DOI: 10.1097/01.alc.0000179220.79356.e5 1720
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 environmental and peer-related explanations for this increase in risky behaviors exist, we now have a better understanding of some of the considerable pharmacologic and neuroanatomic changes occurring in the organism at this age (see Spear, 2000 for review). For example, the dorsolateral prefrontal 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 considerable growth and change, there is currently much concern regarding the long-term consequences of drug exposure during this critical period. Clinical studies are beginning to suggest that there can be marked consequences of chronic exposure during adolescence to a number 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 Alcohol Clin Exp Res, Vol 29, No 9, 2005: pp 1720–1725
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from rodent models of chronic adolescent exposure to either ethanol and/or nicotine. These well-established models provide critical data suggesting that adolescent rats appear particularly sensitive to some of the potentially long-term effects of such exposure.
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 EXPOSURE DURING ADOLESCENCE AFFECTS VULNERABILITY TO ETHANOL-INDUCED IMPAIRMENTS DURING ADULTHOOD
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 ethanol 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 coordination remains unchanged before, two days after, and 16 days after completion of CIE treatment. In contrast, CIE treatment 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 memory 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 drinking performed more poorly while intoxicated than did other subjects. Collectively, the above findings raise the possibility that chronic ethanol exposure during adolescence could alter
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 adolescence (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 adulthood (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 animals through stages of acquisition, extinction, home-cage rest, Pavlovian spontaneous recovery (testing for spontaneous responding on a lever previously paired with reinforcement 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 adolescence displayed (a) quicker acquisition of operant selfadministration (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). Furthermore, 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.,
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1993). Therefore, using microdialysis techniques, our laboratory 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 putative measure of dopamine reuptake) but not increased extracellular levels of dopamine in the NAcc and displayed a more prolonged increase in extracellular levels of dopamine 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 significant 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 presentation, studies examining the neurophysiologic, behavioral, and neurochemical effects of alcohol or nicotine exposure during adolescence were summarized and contrasted. 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 conducted 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 regimen 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 conflict test. In neurophysiologic assessments, ethanol exposure was found to increase parietal cortical 1 to 2 Hz and hippocampal 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 nicotine exposure on event-related potentials were opposite, with adolescent ethanol exposure decreasing cortical N1 amplitude and adolescent nicotine exposure increasing cortical 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. Ethanol 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 preliminary neurochemical analyses, which revealed increased brain levels of hippocampal neuropeptide Y (NPY) after adolescent nicotine exposure. Previous studies have demonstrated 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 adolescent nicotine exposure is a neurochemical index of the antidepressant effects of nicotine. In summary, ethanol and nicotine exposure during adolescence produce differing neurophysiologic, behavioral, and neurochemical consequences. To date, alcohol exposure appears to be associated with a variety of long-term cognitive deficits (i.e., perhaps deficits in attention and memory function). 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 adolescents can have a significantly differential response to nicotine and alcohol relative to adults. Depending on the neurobehavioral function, adolescents can be significantly over-responsive or under-responsive to nicotine and alcohol relative to adults. In other cases, no agerelated differences in response are seen. This pattern of effects suggests selective vulnerabilities circumscribed neurobehavioral systems during adolescence. Determining this pattern of differential drug effects in adolescents can help in the characterization of the critical agerelated differences in neural processes relevant to drug abuse vulnerability.
ADOLESCENT VULNERABILITY TO ALCOHOL OR NICOTINE EXPOSURE
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 adolescent 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 adolescence 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 mecamylamine. 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 impairments are seen after adolescent nicotine exposure despite the fact that during the period of exposure, nicotine improves cognitive performance. Adolescence is an important period to study because the great majority of drug abuse begins during this period when brain development is being completed. ADOLESCENT VULNERABILITIES TO CHRONIC ALCOHOL OR NICOTINE EXPOSURE: SUMMARY AND CONCLUDING COMMENTS
Linda Patia Spear The presentations in this symposium have examined consequences 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 supported 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
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Spear, 2001) effects of ethanol and to the activitysuppressing effects of nicotine (Vastola et al., 2002). Likewise, 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 exceptions to this generality). These adolescent-associated attenuations in ethanol responsiveness appear in part attributable to age-related neural alterations (Silveri and Spear, 2002) as well as to ontogenetic differences in acute tolerance (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). Indeed, 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 nicotine/alcohol co-use. An adolescent insensitivity to certain acute effects of these drugs does not mean that adolescents are protected from long-term adverse consequences after chronic adolescent exposure to nicotine and/or ethanol. Indeed, as detailed 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. Research 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 determine 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 distribution patterns. When comparing efficacy of single versus combined exposure of two drugs across age, additional challenges include choosing across-drug dose equivalencies, determining dependent measures appropriate for assessing effects of each drug alone and in combination, and designing and analyzing the data in ways that permit detection 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
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