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Doi:10.1016/j.pbb.2006.12.00

Pharmacology, Biochemistry and Behavior 86 (2007) 189 – 199 Adolescent cortical development: A critical period of vulnerability for addiction Fulton Crews ⁎, Jun He, Clyde Hodge Bowles Center for Alcohol Studies, School of Medecine, University of North Carolina at Chapel Hill, NC 27599, United States Received 24 July 2006; received in revised form 20 November 2006; accepted 4 December 2006 Available online 12 January 2007 Cortical growth and remodeling continues from birth through youth and adolescence to stable adult levels changing slowly into senescence.
There are critical periods of cortical development when specific experiences drive major synaptic rearrangements and learning that only occurduring the critical period. For example, visual cortex is characterized by a critical period of plasticity involved in establishing visual acuity.
Adolescence is defined by characteristic behaviors that include high levels of risk taking, exploration, novelty and sensation seeking, socialinteraction and play behaviors. In addition, adolescence is the final period of development of the adult during which talents, reasoning andcomplex adult behaviors mature. This maturation of behaviors corresponds with periods of marked changes in neurogenesis, cortical synapticremodeling, neurotransmitter receptors and transporters, as well as major changes in hormones. Frontal cortical development is later inadolescence and likely contributes to refinement of reasoning, goal and priority setting, impulse control and evaluating long and short termrewards. Adolescent humans have high levels of binge drinking and experimentation with other drugs. This review presents findings supportingadolescence as a critical period of cortical development important for establishing life long adult characteristics that are disrupted by alcohol anddrug use.
2006 Elsevier Inc. All rights reserved.
Keywords: Alcohol; Adolescence; Cortical development; Binge drinking; Critical period Introduction: Adolescence; a unique period of development . . . . . . . . . . . . . . . . . . .
Neurotransmitter systems and adolescent development . . . . . . . . . . . . . . . . . . . .
Transcription factor CREB and growth factor BDNF in adolescence . . . . . . . . . . . . . . . .
Adolescent behavior: Risky, motivated, and vulnerable . . . . . . . . . . . . . . . . . . . .
⁎ Corresponding author. Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, 1021 Thurston Bowles Building, CB 7178, Chapel Hill, NC 27599-7178, United States. Tel.: +1 919 966 5678; fax: +1 919 966 5679.
E-mail address: (F. Crews).
URL: (F. Crews).
0091-3057/$ - see front matter 2006 Elsevier Inc. All rights reserved.
F. Crews et al. / Pharmacology, Biochemistry and Behavior 86 (2007) 189–199 Binge drinking during critical periods in cortical development may lead to life long changes of executive function . . . . . 195 1. Introduction: Adolescence; a unique period of of such synaptic changes are not well known, it is speculated that such remodeling is the biological basis of developmentalplasticity where the neurological circuits are effectively shaped Adolescence is a critical period of development during the to adapt to the environmental needs leading to mature adult transition from childhood to adulthood. The ages associated behavior. Such a period of remodeling could also make the with adolescence are commonly considered in humans to be adolescents more vulnerable to external insults and other approximately 12 to 20–25 years of age, and postnatal days (PND) 28 to 42 ) in rodents. Adolescence is best The prefrontal cortex (PFC) and the limbic system, which defined by characteristic adolescent behaviors that include high includes the hippocampus, amygdala, nucleus accumbens levels of risk-taking, high exploration, novelty and sensation (NAc), prefrontal, frontal and orbital frontal cortices and the seeking, social interaction, high activity and play behaviors that hypothalamus, undergo prominent reorganization during ado- likely promote the acquisition of the necessary skills for lescence. Absolute PFC volume declines in adolescence in maturation and independence (). Adolescent humans (as well as in rats behaviors are shared across species, for example, high social Substantial loss of synapses, especially the interactions are found in human adolescents (increased excitatory glutamatergic inputs to the PFC, occurs during the communication with peers and increased number of conflicts adolescent period in humans and nonhuman primates ( with parents) () as In contrast to such well as in adolescent rodents (increased peak level of play adolescent-associated pruning, dopamine and serotinin (5-HT) behavior and affiliative behaviors like huddling, grooming etc.) inputs to PFC increase during adolescence to peak levels well above those seen earlier or later in life ( These behaviors have been suggested to help adolescents ). Cholinergic innervation of PFC develop the social skills needed when they become independent also increases in adolescence to reach mature levels in rats from their family or become senior adults in their group. In ) and humans (). In the rodents, increased social interaction helps guide their food hippocampus, the exuberant outgrowth of excitatory axon choices () and other adult behaviors such as sexual collaterals and synapses during youth are morphologically and aggressive behaviors (Unfor- remodeled and branches within dendritic arbors are pruned tunately, these high levels of novelty/sensation-seeking beha- during adolescent maturation ). Similarly, viors are also strong predictors of drug and alcohol use among significant dendritic pruning and synaptic regression occur in medial amygdala (), nucleus accumbens (NAc) ). This review will cover brain maturation of neuroanat- and the hypothalamus omy, neurotransmission and behavior during adolescence and during adolescence.
present the postulate that the adolescent brain is a critical period Although most synaptic pruning is likely glutamatergic, dopa- of vulnerability for disruption of brain regions important for mine receptor expression peaks in early adolescence (PND28) followed by a one-third loss of receptors during PND35 toPND60 In terms of hypothalamic func- 2. Adolescent brain remodeling tion, adolescent rats often exhibit more prolonged stress-in-duced increases in cortisol than adults (In The adolescent brain is in a unique state of transition as it addition, rats at PND 28 were found to show less stress-induced undergoes both progressive and regressive changes providing Fos-like immunoreactivity in cortical and amygdaloid nuclei a biological basis for the unique adolescent behaviors and the than adult rats (but higher novelty-in- associated changes in behavior during maturation to adult- duced Fos activation in hippocampus during this period hood. Human magnetic resonance imaging (MRI) studies have ). Thus, environmental alterations in gene transcrip- demonstrated an inverted U-shape change in the gray matter tion are unique during adolescence and likely impact the active volume during adolescent period, with a pre-adolescent remodeling of synaptic connections. The following paragraphs increase followed by a post-adolescent decrease review neurochemical markers of adolescent brain remodeling At the cellular levels, these changes to illustrate the high plasticity of normal brain development.
correspond with the marked overproduction of axons and The remodeling of the adolescent brain may represent a critical synapses in early puberty, and rapid pruning in later period of development during which alcohol and drugs may become significant environmental factors modulating brain ). Although the exact mechanisms F. Crews et al. / Pharmacology, Biochemistry and Behavior 86 (2007) 189–199 3. Critical periods of cortical development cortical synaptic pruning and myelination Inhibitory control involves executive func- Critical periods are specific windows during development tions that improve from adolescence to adulthood. Studies when both genetic driven processes and environmental process- measuring behavioral inhibition on a Go-No-Go task and fMRI es, e.g. nature and nurture, interact to establish functional data reveal greater activation of dorsolateral frontal cortex and characteristics. These interactions correspond to structural orbitofrontal cortexes in children, than adolescence, and greater rearrangements of the cerebral cortex that occur during this in adolescence than adults with the adults showing the lowest specific developmental window. As described above, cortical dorsolateral, but equal orbitofrontal activation and greater development in humans occurs over the first 3 decades of life inhibitory control performance ( with grey matter changes correlating with post-mortem findings ). These studies support the concept that the immature of brain regionally different synaptic pruning and myelination brain with excess synapses causes more extensive and less during the transitions from childhood to adolescence to efficient frontal activation and lower performance compared to adulthood. The human visual cortex reaches a peak of synaptic adults that have a more pruned and myelinated frontal cortex that overproduction around the 4th month after birth followed by results in more focused, lower overall activation and faster synaptic elimination starting after that and continuing until reaction times and better performance preschool age at which time synaptic density stabilizes to adult Taken together these studies suggest that remodeling levels Other cortical areas develop at of the cortex during the transitions from youth to adolescence to different ages with dorsal parietal and primary sensorimotor adulthood has functional implications for the entire adult stages regions showing grey matter loss at ages 4–8, and parietal areas of language and spacial orientation changing around ages 11–13 Environmental plasticity of visual cortex development has and prefrontal areas involved in integrating information from been extensively studied. Hubel and Wiesel found that depriving senses, reasoning and other "executive functions" maturing last an eye of light altered cortical responses to light only if the during late adolescence deprivation occurred during a "critical period" of cortical These age-related changes in cortical structure involve improved development. The critical period for visual cortical plasticity is function. Cortical thinning in the left dorsal frontal and parietal defined as the period during which monocular deprivation lobes correlates with improved performance on a test of general (covering one eye) results in a shift in cortical neuronal spiking verbal intellectual functioning between the ages of 5 to 11 responses away from the covered eye and increased spiking (Other studies following individuals from responses to the active eye. The spiking responses are shifted to age 6 through 19 found that individuals with superior the open eye only if the deprivation occurs during the critical intelligence show the greatest changes in frontal cortical period. The critical period for visual cortex plasticity in rodents thickness compared to individuals with high or average overlaps with early adolescence being between PD19 and PD 32 intelligence ). These changes likely are a ). Studies indicate that an activity combination of environment and genetic regulation of cortical dependent synaptic plasticity occurs during this critical period development and overall function. Environmental experiences that allows cortical adjustments to environmental factors. Dark and training are known to induce changes in cerebral cortex rearing delays the critical period of visual cortex development including neurochemical, altered cortical thickness, size of into adulthood likely by decreasing BDNF expression and synaptic contacts and dendritic structure as well as improving GABA synaptic strength Genetic BDNF performance on learning tests overexpression or benzodiazepines administration can acceler- Learning in humans during studying for exams ( ate the appearance of the critical period of visual cortical or practicing juggling ) alters development. Environment and genetic programming interact to cortical structure consistent with environment contributing to regulate synaptic organization during the critical period structural changes in brain. These developmental processes are resulting in a mature cortex. The mature cortex is stable and thought to underlie time-limited windows when specific does not undergo the dramatic shift in cortical synaptic plasticity experiences can drive development, e.g. critical periods of with monocular deprivation or dark rearing. Thus, early plasticity or learning that can only occur during these critical adolescence is a critical period for visual cortical maturation.
period windows (For example, learning a Ethanol treatment has been shown to lead to a permanent second language is thought to be optimal during a critical period impairment of visual neocortex plasticity and to be particularly of development (The complexity toxic to adolescent brain. Studies in ferrets have found that of higher brain functions makes it difficult to relate synaptic ethanol treatment before the critical period prevents ocular rearrangements to alterations in function. The synaptic rearran- dominance from occurring in neurons during the critical period gements and increased myelination of frontal cortical areas in mid to late adolescence could be involved in altered executive iological single unit recording indicates that alcohol exposure functions. Behavioral studies show that performance on tasks weakened neuronal orientation selectively while preserving including inhibitory control, decision making and processing robust visual responses Further, optical speed continues to develop during adolescence. During imaging maps of intrinsic synaptic signaling from the eyes to the adolescence tasks of selective attention, working memory and visual cortex are highly contrasted in controls following the problem solving improve consistently correlating with frontal critical period of synaptic ocular dominance, but have little F. Crews et al. / Pharmacology, Biochemistry and Behavior 86 (2007) 189–199 contrast or no ocular dominant columns after ethanol adminis- a major contribution of cortical remodeling. In adolescent tration. Disruption of ocular dominant columns in visual cortex monkeys significant changes occur in pre- and post-synaptic is known to reduce visual acuity and monocular deprivation markers of GABAergic synapses in the prefrontal cortex during during the critical period essentially creates a blind eye due to adolescence ). Generally, basal levels of altered synaptic connections These GABAA receptor-mediated chloride uptake are greater in the studies indicate that alcohol exposure preceding and during cortex of adolescents than that of adults () critical periods of cortical development disrupt cortical devel- and the responsiveness of cortical GABAA neurotransmission to opment resulting in reduced function permanently. Studies of stressors decreases from adolescence to adulthood ( binge drinking induced brain damage in rats have found that In hippocampus, the expression of GABA transporter 1 adolescent forebrain is particularly sensitive to ethanol induced (GAT-1) and glutamic acid decarboxylase (GAD), e.g. GABA neurodegeneration ). Further, adolescent synthase, peak around early infancy brain has been found to be particularly sensitive to ethanol although hippocampal GABAB receptor regulation of induced inhibition of neurogenesis, the formation of new synaptic transmission does not mature until adolescence neurons ). These studies indicate that ethanol (PND35) (). GABAA receptors are disrupts cortical remodeling during critical periods and is heterogeneous group of receptors composed of two alpha, one particularly neurotoxic to the adolescent brain.
beta and two delta or other subunits. There are multiple alpha Ethanol is known to interact with glutamatergic NMDA subunits that can contribute to GABAA receptors and varied receptors, GABAa receptors, DA pathways, CREB transcrip- subunits modulate GABAA receptor function and responsive- tion, and neurogenesis. Each of these systems is undergoing ness to GABA, anti-anxiety drugs, neurosteroids, alcohol and extensive remodeling in adolescence. The following sections other modulators of GABA transmission. In fact, the subunit review the remodeling of these neurochemical markers known composition of GABAA receptor subunits largely determines the to be sensitive to ethanol.
pharmacological and electrophysiological properties of GABAneurotransmission 4. Neurotransmitter systems and adolescent development GABAA subunits undergo dramatic postnatal reorgani-zation ). The alpha1 subunit that contributes to 4.1. Glutamate and NMDA receptor systems sedative, amnestic and anticonvulsant actions of GABA under-goes a dramatic increase in the frontal cortex between youth (10 The binding of cortical glutamate to its NMDA receptor PND) and adolescence (30 PND) followed by a significant de- subtype peaks in early adolescence, and declines significantly cline in the transition to adulthood (90 PND) becoming rela- thereafter, with a loss of one-third of NMDA receptors by tively stable at later ages This likely represents PND60 (). Such synaptic remodeling of GABAergic synapses. Alpha2 and Alpha3 pruning contributes to the loss of excitatory glutamate input to subunits show a similar increase from youth to adolescence, in NAc (and a reduction in frontal cortex, however, alpha2 stays elevated through adult- accumbal NMDA receptors hood and alpha3 GABAA subunits decline slowly reaching during adolescent brain maturation. Interestingly, long-term statistical significance at 9 months. Alpha5 GABAA subunits are potentiation (LTP), a measurable increase in synaptic strength high in youth and in different brain regions decline through and a form of neuroplasticity, is more frequently found in NAc of adolescence into adulthood. Alpha2, 3 and 5 subunits contribute adolescent mice compared to adults consistent with adolescence to anxiolytic and other properties of GABA modulators being a highly plastic period of mesolimbic brain development (Fritschy and Brunig, 2003). Interestingly, the alpha2 subunit (This plasticity was also demonstrated in of the GABAA receptor complex, whose expression steadily other limbic regions that are believed to be involved in drug increases across the brain from early youth throughout addiction, including amygdala (VTA adolescence has been implicated in the genetics (and hippocampus ).
of alcoholism. A sequence difference in the alpha2 subunit of the Alcohol and other drugs are known to modulate glutamatergic GABAA receptor has been found to be about twice as common in transmission and alter limbic brain development ( alcohol dependent German patients than matched controls ). Therefore, glutamate and NMDA receptor systems play a consistent with contributing to genetic predisposition to crucial role in the neurochemical remodeling in adolescents, alcoholism (Interestingly, chronic alcohol in especially in limbic brain regions that are highly plastic and adults decreases cerebral cortical alpha2 and alpha3 subunits actively undergoing remodeling. The impact of alcohol and resulting in loss of benzodiazepine recognition sites and likely other illicit drugs on the development of glutamatergic synapses changing overall GABA transmission in these brain regions is critical for understanding the particular Studies in adolescents have not been done, however, alcohol vulnerability of adolescents to drug addiction.
induced changes in GABA subunits during the active period ofcortical development might result in differential stabilization of 4.2. GABAergic systems adult GABAA receptor synaptic organization that remaindisrupted for long periods in adulthood. The maturation of GABAergic (γ-aminobutyric acid) neurotransmission, as the GABAergic neurotransmission from infancy to adolescence to major inhibitory neurotransmitter in the brain, that likely makes adulthood likely contributes to inhibitory interneuron fine- F. Crews et al. / Pharmacology, Biochemistry and Behavior 86 (2007) 189–199 tuning of synaptic inputs improving discrimination of signals expressed in humans, cats and rodents at birth, but decline and more efficient processing. Disruption by alcohol and other dramatically during adolescence addictive drugs during the adolescent remodeling of GABA- mediated inhibitory control of neuronal circuitry could alter susceptibility to alcohol dependence and other drug addiction in NAc is reported to be approximately 4-fold lower in adolescent rats (PND30-40) than either younger rats (PND10-15) or matureadults (PND60-80) ). Interestingly, low 5-HT 4.3. Dopaminergic systems activity in adolescence has been suggested contribute tocommon adolescent behaviors such as hypersensitivity to Dopaminergic transmission contributes to attention, reward, mild stressors, increased anxiety and alcohol drinking movement, hormone regulation and multiple other important In contrast to the alteration in serotonin physiological processes. Postnatal reorganization of dopami- receptors during adolescence, serotonin transporters steadily nergic neurotransmission is brain regional and receptor subtype- increase from PND7 to adulthood without significant pruning in specific. In rat frontal cortex, entorhinal cortex and hippocam- striatum and NAc Studies modeling pus, dopamine D1, D2 and D4 receptors rise several fold from adolescence binge drinking in rats have found marked increases PND7 to PND35, e.g. adolescence, and then stabilize to in adult levels of serotonin transporters ().
adulthood ). In striatum and Thus, serotonin neurotransmission undergoes dramatic remo- nucleus accumbens (NAc) dopamine receptors are overpro- deling from youth through adolescence into adulthood and it is duced with subsequent pruning of approximately one-third sensitive to alcohol and drug disruption.
during adolescent suggesting maturational remodeling of motor In summary, major neurotransmitter systems are not mature and reward pathways ( at birth and postnatal brain development continues through Furthermore, dopamine D3 receptors do adolescence, with remodeling most pronounced in frontal and not reach peak levels until adulthood (PND60) in striatum, NAc limbic regions.
and olfactory tubercle ). In contrast,dopamine transporters increase 6–7 fold steadily throughout 5. Transcription factor CREB and growth factor BDNF in brain from PD7 to PD60 in striatum in contrast to the remodeling of dopamine receptors in adolescent striatum(). This substantial postnatal remodeling of The cAMP-response element binding protein (CREB) is an dopamine neurotransmission during adolescence may contrib- important mediator for the differentiation and maturation of ute to a stabilization of behaviors established during adoles- CNS neurons. CREB is also critical for induction of trophic cence. Alcohol and drug taking may alter the maturation of factors such as BDNF, for neuronal vitality and for learning and dopamine neurotransmission during adolescence contributing to altered development of attitudes, actions and social rewards.
phosphorylation, CREB is activated to propagate signals fromsynapses to the nucleus to the expression of genes necessary for 4.4. Serotonergic systems synaptic plasticity (). As such a key transcriptional factor for Serotonergic neurotransmission undergoes reorganization neuronal growth, it is not surprising that the expression of CREB during postnatal development and is important for mood, sleep, can play a critical role in postnatal neurochemical remodeling.
anxiety and many other complex behaviors. In humans and rats, Phospho-CREB (pCREB), the transcriptionally active form of 5-HT neurons are generated prenatally CREB, is highly expressed in early postnatal development ) with brain 5-HT levels peaking early in (PND7) and declines during adolescence to adult levels in both life, then decreasing to adult levels ( hippocampus and cortex (Additionally, Postnatal reorganization of developing CREB activation occurs prior to the expression of BDNF (brain- serotonergic projections is exemplified by fluctuations of the derived neurotrophic factor) and neurotrophin-3 (NT3) ( number of serotonergic synapses during this period, 5HT , consistent with CREB being upstream and synapses reach adult levels at PND14 and then in rat basal activating transcription of these neurotrophic factors. BDNF is forebrain drop to significantly lower levels during early involved in the regulation of neuronal differentiation, survival adolescence (). The and neuroplasticity as well as being linked with a variety of reorganization of 5-HT receptor expression is also pronounced neurological and psychiatric disorders (epilepsy, mood disorder, during development, likely relating to reorganization of bipolar depression) in children, adolescents as well as adults serotonergic innervation patterns. For example, 5-HT2A recep- tors reach cortical peak expression just before adolescence and CREB and BDNF interact in a variety of brain regions and are then progressively decline to adult levels correlated with known to play a critical role in addition ).
increased innervation and pruning of 5-HT axons in rat and Thus, the developmental alterations in CREB-BDNF contribute monkey (Similarly, 5-HT7 to continuous modeling of brain through youth, adolescence into receptors exhibit transient expression patterns in striatum and adulthood and are vulnerable to alcohol and drug induced hippocampus (5-HT1A receptors are highly disruption of development.
F. Crews et al. / Pharmacology, Biochemistry and Behavior 86 (2007) 189–199 6. Neurogenic processes in adolescent brains into action (). Increased adolescentreward sensitivity, motivation and action is likely related to the Although neurogenesis is primarily an early developmental synaptic remodeling of striatal, limbic and frontal brain regions process with most neurons being formed in the prenatal and as the final stage of development to adulthood.
early postnatal periods, it continues into adulthood within In addition to reward circuits, a variety of other neural specific adult brain regions including the forebrain subven- systems also exhibit developmental changes during adolescence tricular zone (SVZ) and hippocampal dentate gyrus (DG) where that lead to behavioral and cognitive alterations. For example, neurogenesis continues into senescence. Generating and evidence suggests that a variety of self-regulatory executive integrating new neurons into preexisting neuronal circuits is functions are still maturing during adolescence. For this reason, believed to enable the hippocampus to adapt to novel and more adolescents are in the sometimes unfortunate situation of having complex situations (The contribution of poor judgment and lack of impulse control even though they are adult hippocampal neurogenesis to learning and memory ( driven to seek increasing levels of novelty and external stimu- as well as mood and affective state ( lation. A variety of brain systems mediates impulse control ) is supported by many studies. Adolescent neurogenesis ) but maturation of prefrontal cortical and its role in the brain remodeling and unique adolescent systems appears to track development of executive functions behaviors have not been investigated. Studies have indicated that adolescents have higher levels of neurogenesis in the Adolescence is also characterized by the appearance of hippocampus and adolescent brain strong emotional states where some individuals experience neurogenesis is very sensitive to alcohol-induced inhibition striking changes in mood that are sometimes difficult to (). Disruption of neurogenesis by drugs and distinguish from clinical syndromes, such as depression alcohol during adolescence could produce long-lasting changes An understanding of mood in adulthood.
changes during adolescence may be gained from evaluatingneurobiological systems that regulate adult mood disorders.
7. Adolescent behavior: Risky, motivated, and vulnerable Along these lines, one potentially important outcome ofdevelopmental changes in gene transcription (e.g., CREB) and As just noted, the adolescent brain undergoes remodeling in growth factor (e.g., BDNF) expression is altered neurogenesis a variety of structural and functional regions, particularly (see above). It has been hypothesized that decreased neurogen- corticolimbic and frontal regions known to regulate emotional esis in the hippocampus is a mechanism underlying mood as well as analytical and executive processes. Simultaneous changes, such as depression ( with these changes, adolescents demonstrate new behaviors that which are common during adolescence. Although the are associated with acquisition of adult cognitive and emotional functional consequences of altered neurogenesis to adolescent repertoires (These are normal adaptive changes behavioral changes remain to be studied, some noteworthy that help usher the adolescent into adulthood. However, linkages exist. For example, stress and elevated stress adolescents also exhibit increased health-risk behaviors that hormones, which are hallmarks of adolescence, alter neurogen- represent the leading causes of morbidity and mortality among esis and precipitate changes in mood the adolescent age group (). Disruption of adolescent development by environmental factors, particularly Antidepressant drugs that target serotonin and alcohol and other abused drugs might produce subtle changes norepinephrine systems, both of which change during adoles- other than the known pronounced mortality that have a delayed cence, increase hippocampal neurogenesis ( impact on the quality of adult life. For this reason, it is important When taken together to understand adolescent behavior and neurobiology in the with evidence that antidepressants also increase serotonin, context of the developing brain in order to appreciate the CREB and BDNF activity ), these adaptive changes within a critical period of acquisition of adult data suggest that developmental changes in these pathways may cognitive and emotional repertoires.
underlie some of the mood alterations that characterize One of the most pronounced changes in adolescent behavior adolescence. In addition, evidence shows that enriched is the characteristic increased risk taking. Epidemiological environment and exercise are associated with increased mood studies show that human adolescents engage in more risky and neurogenesis, whereas stress is associated with depression behavior, which includes hazardous driving, unprotected sex, and decreased neurogenesis ( and substance abuse as compared to adults ( ). The adolescent trait of impulsivity is also These behaviors are associated with low levels of normalized by enriched rearing during adolescence ( anxiety regarding the potential for harm ). Moreover, adolescents who have enriched envi- ). One explanation for age-related differences in risk taking ronments in the form of socially active friends and engaged is the characteristic reduction in reward sensitivity that leads parents exhibit fewer behavioral problems and engage in less adolescents to seek higher levels of novelty and external risky behavior ). Thus, it is plausible that stimulation. Changes in reward sensitivity may reflect matura- both developmentally and environmentally regulated changes in tional differences in mesolimbic neural circuits ( neurogenesis may underlie alterations in mood and behavior which regulate the translation of motivation that accompany adolescence.

F. Crews et al. / Pharmacology, Biochemistry and Behavior 86 (2007) 189–199 Overall, adolescents exhibit a variety of behavioral changes 9. Binge drinking during critical periods in cortical that reflect normal development of brain systems. Paradoxical- development may lead to life long changes of executive ly, these developmental changes also create conflicts in behavioral repertoires that mark the unique vulnerability ofthis developmental period. A few of these have been discussed The effects of alcohol on adolescent brains are different from above in terms of specific systems that may regulate specific those on adults. Adolescents are less sensitive to the sedative behaviors. Ultimately, however, a more complete understanding effects of alcohol (which allows them of the paradoxical properties of adolescent behavior is likely to to binge drink, however, they are more vulnerable to alcohol- require a multidisciplinary systems approach that integrates induced neurotoxicity ). The increase in developmental, behavioral, and neural analyses.
sensitivity of the adolescent brain to toxicity and the dynamicsynaptic remodeling of the maturing adolescent brain may 8. Adolescent alcohol abuse is common enhance the strong learning components of heavy drinkingbehaviors and the loss of important self-control and goal setting Alcohol use among adolescents is common. As described components of the maturing brains executive centers. Indivi- earlier, adolescent high risk-taking, thrill and novelty-seeking duals who start drinking before the age of 15 are four times behaviors promote heavy drinking and other drug experimen- more likely to become alcohol dependent at some time in their tation. Individuals in their teens and early twenties are among life (Current studies indicate that the heaviest episodic drinkers. For example, among U.S. high 25–35% of high school students began drinking before the age school students 12% of 8th graders (13–14 years of age), 22% of 13 ). Studies of adolescent individuals with of 10th graders and 28% of 12th grade seniors reported heavy alcohol use disorder have found smaller prefrontal grey and episodic drinking within the past 2 weeks white matter volumes than age matched controls. Lower According to the National Institute of Drug Abuse, 82% prefrontal volumes correlated with a higher maximum number of adolescents have tried alcohol by the time they reach their of drinks per drinking episode (It is senior year in high school. For college students 44% binge drink likely that both genetics and environment (heavy drinking) every two weeks and 19% are frequent binge drinkers, having contribute to the alcohol use disorder and lower prefrontal more than 3 binge drinking episodes per week ( volumes in adolescence with alcohol use disorder. Studies of Thus, adolescents are often drinking large quantities of social drinkers have found that the heaviest binge drinkers have more negative moods and performed worse on executive Fig. 1. Adolescent alcohol abuse disrupts frontal cortical development and maturation of executive function. This schematic diagram emphasizes the normal focusingof cortical excitation during cerebral tasks that occurs during the transition from adolescent to adult as indicated by the upward narrowing arrow. Frontal corticalremodeling is associated with improved performance at tasks and stabilization of reasoning, impulse control, goal setting, maturation of risk taking, reward sensitivity,motivation, and emotional states. Adult executive functions stabilize after adolescence with a slow decline in senescence. Individuals who have talent (genetics) andtraining (environment) are most likely to achieve their best abilities at the juncture of adulthood. Individuals who binge drink during adolescence damage and disruptforebrain cortical development during a critical period of behavioral and cortical maturation. Binge drinking interferes with cortical remodeling as illustrated by thelarge vertical slightly downward arrow that does not focus. Following adolescence many individuals spontaneously or through therapy reduce their drinking andpartially recover executive functions, although they remain lower in ability than those who develop normally. Other individuals remain heavy drinkers continuing todrink. Through the life course many will escalate drinking due to stress, tolerance development, avoidance of negative withdrawal states and other factors that drivethem to therapy in their mid-adult years. This model suggests that interventions to reduce adolescent drinking will greatly improve abilities of many individuals andreduce overall lifetime alcoholism and addiction.
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