Timing Eclipses Amount: The Critical Importance of Intermittency in Alcohol Exposure Effects.

Frequency and duration of ethanol (EtOH) exposures influence the consequences of those experiences, with evidence building from basic science studies in rats and mice that intermittent alcohol access (IAA) typically produces a greater escalation of EtOH intake than more continuous alcohol access (CAA). IAA also better simulates human use patterns where alcohol levels typically clear from the body between periods of use. A variety of mechanisms have been proposed to contribute to the enhanced intake of EtOH induced by IAA, including a possible attenuation in the aversive effects of EtOH, although further studies are needed to address this and other possibilities. Neural differences include indications of an IAA-associated increase in NR2B receptors that is not evident with CAA; although little studied, alterations in other neural and neurotransmitter systems are evident as well. Many gaps in understanding of IAA/CAA effects remain. Further work is needed to characterize neural mechanisms underlying these effects, consequences of IAA/CAA on EtOH effects beyond intake, and the impact of stress and environmental variables on these differences. IAA/CAA studies to date have also largely been limited to males and to adult animals, and hence, more studies examining IAA/CAA across sex and age are needed. Such additional work is essential to determine unique contributors to IAA-induced elevations in EtOH intake that may provide important insights for the development of new prevention/intervention strategies for heavy alcohol use and abuse.

Adolescent but not adult Sprague-Dawley rats display goal-directed responding after reward devaluation.

Alcohol drinking is typically initiated in adolescence, with use sometimes escalating to problematic levels. Escalation of drinking is often associated with a shift in drinking motives, with goal-directed initial use later transitioning to more habitual behavior. This study assessed whether adolescents are more sensitive than adults to habit formation when indexed via insensitivity to reward devaluation in an operant task for food reward. Adolescent and adult Sprague-Dawley rats were trained on either a random ratio (RR) or random interval (RI) schedule before undergoing devaluation. Adolescent animals on both schedules increased the number of lever presses across all training days. In contrast, adults in the RR group increased the number of lever presses across days whereas RI adults remained relatively stable. In response to pellet devaluation, only adolescents exhibited reduced responding, suggestive of goal-directed behavior, whereas no age differences were evident following control (home cage chow) devaluation. Contrary to our hypothesis, adolescents (but not adults) displayed goal-directed responding indexed via sensitivity to reward devaluation. These findings suggest that adolescents are not necessarily more likely to develop habits than adults, and hence other factors may contribute to the greater propensity of adolescents to engage in and escalate alcohol use.

Voluntary Binge Consumption of Ethanol in a Sweetened, Chocolate-Flavored Solution by Male and Female Adolescent Sprague Dawley Rats.

BACKGROUND: The still maturing adolescent brain may be particularly vulnerable to lasting consequences of ethanol (EtOH) exposure. Yet, human adolescents are the age group most likely to engage in binge drinking (a pattern of drinking leading to blood EtOH concentrations (BECs) of 80 mg/dl or greater). Most studies to date assessing the long-term effects of adolescent EtOH exposure in outbred rodent populations have either used experimenter-administered EtOH to produce BECs in the binge range or assessed voluntary intake of EtOH at well below binge levels. Beginning with a modified schedule-induced polydipsia (SIP) procedure, this study examined the suitability of several approaches to induce voluntary binge-like consumption during adolescence in an outbred rat strain. METHODS: Adolescent male and female Sprague Dawley rats were food deprived to 85% projected free-feeding weights beginning on postnatal day (P) 24 and were given 30 minutes of access to 10% EtOH in chocolate Boost® or Boost® alone daily from P28 to P41 (followed later by their daily allocation of food). Animals were tested within operant chambers (Exp. 1a, 1b and Exp. 2) or home and novel cages (Exp. 3). Animals received either scheduled delivery of banana pellets to examine SIP (Exp. 1a,b) or massed pellet presentation (Exp. 2 and Exp. 3). Blood samples were collected via the lateral tail vein on P33 and P41. RESULTS: Intakes produced BECs frequently in the binge range (>80 mg/dl) and modeled binge-like consumption patterns, with high consumption days typically followed by 1 to 2 days of lower consumption; this variability was less evident with Boost® alone. Consumption was not schedule induced and was generally high across all studies, although consumption in males appeared to be particularly pronounced when animals were tested in the presence of their cage mate. CONCLUSIONS: Binge-like patterns of EtOH consumption were produced using these procedures in adolescent Sprague Dawley rats of both sexes and may prove to be a useful model for work examining the short- and long-term consequences of high levels of voluntary EtOH intake in adolescence.

Rats exposed to intermittent ethanol during late adolescence exhibit enhanced habitual behavior following reward devaluation.

The brain undergoes substantial maturation during adolescence, and repeated exposure to ethanol at this time has been shown to result in long-lasting behavioral and neural consequences. During the broad period of adolescence, different neuronal populations and circuits are refined between early and late adolescence, suggesting the possibility that ethanol exposure at these differing times may lead to differential outcomes. The goal of the current study was to evaluate the impact of adolescent intermittent ethanol (AIE) during early and late adolescence on the formation of goal-directed and habitual behavior in adulthood. Male and female Sprague-Dawley rats were exposed to ethanol via intragastric gavage (4.0 g/kg, 25% v/v) every other day from postnatal day (P) 25-45 or P45-65, considered early and late adolescence, respectively. In adulthood (~P70 early or ~ P90 late), rats were gradually food-restricted and began operant training on a fixed ratio 1 schedule. Rats were then transitioned onto random interval schedules and eventually underwent a sensory-specific satiation procedure as a model of reward devaluation. Few differences as a result of adolescent ethanol exposure were found during instrumental training. Following reward devaluation, rats exposed to water and ethanol during early adolescence exhibited reductions in lever pressing, suggestive of a goal-directed response pattern. In contrast, late AIE males and females demonstrated persistent responding following both devalued and non-devalued trials, findings representative of a habitual behavior pattern. The shifts from goal-directed to habitual behavior noted only following late AIE contribute to the growing literature identifying specific behavioral consequences as a result of ethanol exposure during distinct developmental periods within adolescence. More work is needed to determine whether the greater habit formation following late AIE is also associated with elevated habitual ethanol consumption.

The effects of age, sex, and handling on behavioral parameters in the multivariate concentric square field™ test.

The multivariate concentric square field™ (MCSF) is a complex and ethologically relevant apparatus that is designed to measure several behavioral parameters within the same test session including risk-taking, risk-assessment, shelter-seeking (anxiety relieving), exploration, and general activity. While several studies have behaviorally and pharmacologically validated the use of the MCSF in adults, far fewer have used adolescents. Given the well-established link between adolescence and risk-taking, it is important to validate use of the MCSF in adolescence. The present study compared the effects of age, sex, and handling on behavioral categories in the MCSF. In addition, principal component analyses were used to compare the underlying behavioral components in adolescent and adult Sprague-Dawley rats. Results revealed that handling increased risk-taking and reduced shelter-seeking. Females were more exploratory than males, but no compelling age differences in risk-taking or risk-assessment were found. Principal component analyses revealed six major principal components for both adolescents and adults with the first and second components consisting mainly of center/center circle, risk-assessment, and shelter-seeking variables in adolescence, and general activity and center/center circle variables in adults. These results confirm age differences in the underlying behavioral components in the MCSF.

Sensitivity to ethanol and other hedonic stimuli in an animal model of adolescence: implications for prevention science?

Age-related patterns of sensitivity to appetitive and aversive stimuli seemingly have deep evolutionary roots, with marked developmental transformations seen during adolescence in a number of relatively ancient brain systems critical for motivating and directing reward-related behaviors. Using a simple animal model of adolescence in the rat, adolescents have been shown to be more sensitive than their adult counterparts to positive rewarding effects of alcohol, other drugs, and certain natural stimuli, while being less sensitive to the aversive properties of such stimuli. Adolescent-typical alcohol sensitivities may be exacerbated further by a history of prior stress or alcohol exposure as well as by genetic vulnerabilities, permitting relatively high levels of adolescent alcohol use and perhaps an increased probability for the emergence of abuse disorders. A number of potential (albeit tentative) implications of these basic research findings for prevention science are considered.

Heightened stress responsivity and emotional reactivity during pubertal maturation: Implications for psychopathology.

This commentary reviews and reflects on the studies of this special section: studies that collectively provide compelling evidence for meaningful changes in stress- and emotionally reactive psychophysiological systems with the transition from middle childhood into adolescence. The observed changes were complex and often overlaid upon ontogenetic differences in basal levels of activation of these systems. Maturational increases in responsiveness to stressors were stressor dependent and differentially expressed across autonomic and hormonal measures. Pubertal status increased the impact of some affective valence manipulations, although not significantly influencing others, including negative affect-related potentiation of startle/reflexes. Such ontogenetic increases in stressor and affect sensitivity may have implications for developmental psychopathology. Developmental increases in stressor reactivity may normally aid youth in responding adaptively to the challenges of adolescence, but may result in stress dysregulation among at-risk adolescents, increasing further their vulnerability for psychopathology. Pubertal-related increases in sensitivity to emotionally laden stimuli may exacerbate individual predispositions for exaggerated affective processing, perhaps contributing to the emergence of psychological disorders in these youth. Together, these studies, with their innovative use of autonomic, reflexive, and hormonal measures to index age- and pubertal-related changes in reactivity to stressors and affective stimuli, provide promising directions for future research. Some of these, along with a few cautionary notes, are outlined.

Voluntary elevated ethanol consumption in adolescent Sprague-Dawley rats: Procedural contributors and age-specificity.

Alcohol consumption is typically initiated during adolescence, with the incidence of binge drinking (production of blood ethanol concentrations [BECs] > 80 mg/dL) peaking during this stage of development. Studies in outbred rats investigating the consequences of adolescent ethanol exposure have typically employed intragastric, vapor, or intraperitoneal administration to attain BECs in this range. While these procedures have yielded valuable data regarding the consequences of adolescent exposure, they are varyingly stressful, administer the full dose at once, and/or bypass digestion. Consequently, we have worked to develop a model of voluntary elevated ethanol consumption in outbred adolescent Sprague-Dawley males and females, building on our previous work (see Hosová & Spear, 2017). This model utilizes daily 30-min access to 10% ethanol (v/v) in chocolate Boost® from postnatal day (P)28-41. Experiment 1 compared intake levels between (1a) animals given either ball-bearing or open-ended sipper tube tips for solution access, (1b) animals separated from their cage mate by wire mesh or isolated to a separate cage during solution access, (1c) animals given solution access with or without simultaneous access to banana-flavored sugar pellets, and (1d) animals that were either moderately food-restricted or fed ad libitum. Experiment 2 compared intake levels between animals given daily solution access and animals given access only on a "Monday-Wednesday-Friday" intermittent schedule. Experiment 3 compared adolescent and adult (P70-83) consumption using the finalized procedure as based on the results of Experiments 1 and 2. As in our previous work, consumptions well within the binge range were produced on some days, with high-consumption days typically followed by several days of lower consumption before increasing again. Sipper tube type (1a) and simultaneous pellet access (1c) did not affect consumption, while intake was significantly higher in non-isolated (1b), food-restricted (1d), daily-access (2), and adolescent (3) animals. However, although ethanol intake was higher in food-restricted animals, the resulting BECs were equivalent or higher in non-restricted animals, likely due to a hepatoprotective effect of moderate food restriction. Post-consumption intoxication ratings correlated with BECs and were notably higher in adults than adolescents, despite the lower voluntary consumption levels of adults, confirming prior reports of the attenuated sensitivity of adolescents to ethanol intoxication relative to adults. The final model utilized ball-bearing sipper tube tips to provide daily access to 10% ethanol in chocolate Boost® to free-feeding adolescent animals separated from their cage mate by wire mesh, with no food provided during solution access. This easy-to-implement model is effective in producing elevated voluntary ethanol consumption in adolescent, but not adult, Sprague-Dawley rats.

Prenatal ethanol exposure attenuates sensitivity to the aversive effects of ethanol in adolescence and increases adult preference for a 5% ethanol solution in males, but not females.

The present set of experiments investigated the effects of a moderate dose of ethanol (2 g/kg; 20% v/v intragastrically) during late gestation (G17-20 [gestational day]) on ethanol-induced conditioned taste aversion (CTA) in adolescence, and on ethanol consumption during adolescence and early adulthood. In experiment 1, male and female Sprague-Dawley rats were given 30-min access to a sweetened "supersaccharin" (SS) solution or sodium chloride (NaCl), followed by an intraperitoneal injection of 20% ethanol (0, 1, 1.25, or 1.5 g/kg) for three conditioning/test sessions. Among animals conditioned with SS, prenatally ethanol-exposed males exhibited attenuated ethanol-induced CTA relative to males prenatally gavaged with water or non-manipulated, whereas prenatal treatment had no effect on CTA in females. Among animals conditioned with NaCl, there were no exposure group differences in males, with modest evidence for attenuated CTA in prenatally ethanol-exposed females. In experiment 2, the effects of prenatal ethanol exposure on ethanol consumption in adolescents (P35 ± 1 day [postnatal day]) and adults (P56-60) were explored. At the beginning of the dark cycle, pair-housed rats were given three bottles containing 0, 5, and 10% ethanol for 18 h every other day (i.e., Monday, Wednesday, Friday) for 3 weeks. Relative to water controls, adult males prenatally exposed to ethanol showed greater preference and more intake (g/kg) of 5% ethanol, while showing lower intake of 10% ethanol. These intake and preference differences were not evident in adolescent males. Among females at both ages, ethanol-exposed animals showed lower preference and intake (g/kg) of 5% ethanol than their water-exposed controls. Thus, moderate ethanol exposure during late gestation produced a largely male-specific attenuation in the aversive effects of ethanol during adolescence that could contribute to later increases in preference and intake of a 5% ethanol solution, although this emergent effect was not evident in adolescence (or in females), but only manifested in adulthood.

Adolescent but not adult rats exhibit ethanol-mediated appetitive second-order conditioning.

BACKGROUND: Adolescent rats are less sensitive to the sedative effects of ethanol than older animals. They also seem to perceive the reinforcing properties of ethanol. However, unlike neonates or infants, ethanol-mediated appetitive behavior is yet to be clearly shown in adolescents. Appetitive ethanol reinforcement was assessed in adolescent (postnatal day 33, P33) and adult rats (P71) through second-order conditioning (SOC). METHODS: On P32 or P70, animals were intragastrically administered ethanol (0.5 or 2.0 g/kg) paired with intra-oral pulses of sucrose (CS(1), first-order conditioning phase). CS(1) delivery took place either 5-20 (early pairing) or 30-45 minutes (late pairing) following ethanol administration. The time interval between CS(1) exposure and ethanol administration was 240 minutes in unpaired controls. On P33 or P71, animals were presented the CS(1) (second-order conditioning phase) in a distinctive chamber (CS(2), second-order conditioning). Then they were tested for CS(2) preference. RESULTS: Early and late paired adolescents, but not adults, had greater preference for the CS(2) than controls, a result indicative of ontogenetic variation in ethanol-mediated reinforcement. During the CS(1)-CS(2) associative phase, paired adolescents given 2.0 g/kg ethanol wall-climbed more than controls. Blood and brain ethanol levels associated with the 0.5 and 2.0 g/kg doses at the onset of each conditioning phase did not differ substantially across age, with mean blood ethanol concentration of 38 and 112 mg%. CONCLUSIONS: These data indicate age-related differences between adolescent and adult rats in terms of sensitivity to ethanol's motivational effects. Adolescents exhibited high sensitivity for ethanol's appetitive effects. These animals also showed ethanol-mediated behavioral activation during the SOC phase. The SOC preparation provides a valuable conditioning model for assessing ethanol's motivational effects across ontogeny.

Binge Drinking's Effects on the Developing Brain-Animal Models.

Adolescence typically is a time of experimentation, including alcohol use and, particularly, binge drinking. Because the brain is still developing during adolescence, such exposure could have long-lasting effects. Animal models and adolescent intermittent ethanol exposure (AIE) paradigms have been used to help elucidate the consequences of adolescent binge drinking. These studies have identified cognitive deficits, particularly in challenging cognitive tasks, and behavioral alterations such as greater risk preferences, impulsivity, and disinhibition. AIE also is associated with changes in affect when the animals reach adulthood, including increased social anxiety and, sometimes, general anxiety. Animal models have demonstrated that AIE can result in retention of certain alcohol-related adolescent phenotypes (i.e., reduced sensitivity to alcohol's aversive effects and increased sensitivity to alcohol's rewarding effects) into adulthood, which may motivate continued elevated alcohol use. The detrimental effects of adolescent alcohol exposure extend to a diversity of lasting alterations in the brain, including reduced neurogenesis, increased proinflammatory responses, changes in gene expression through epigenetic mechanisms, and alterations in the activities of various neurotransmitter systems. Further exploration of these mechanisms in animal models and humans may lead to improved prevention and intervention efforts.

Stress alters social behavior and sensitivity to pharmacological activation of kappa opioid receptors in an age-specific manner in Sprague Dawley rats.

The dynorphin/kappa opioid receptor (DYN/KOR) system has been identified as a primary target of stress due to behavioral effects, such as dysphoria, aversion, and anxiety-like alterations that result from activation of this system. Numerous adaptations in the DYN/KOR system have also been identified in response to stress. However, whereas most studies examining the function of the DYN/KOR system have been conducted in adult rodents, there is growing evidence suggesting that this system is ontogenetically regulated. Likewise, the outcome of exposure to stress also differs across ontogeny. Based on these developmental similarities, the objective of this study was to systematically test effects of a selective KOR agonist, U-62066, on various aspects of social behavior across ontogeny in non-stressed male and female rats as well as in males and females with a prior history of repeated exposure to restraint (90 min/day, 5 exposures). We found that the social consequences of repeated restraint differed as a function of age: juvenile stress produced substantial increases in play fighting, whereas adolescent and adult stress resulted in decreases in social investigation and social preference. The KOR agonist U-62066 dose-dependently reduced social behaviors in non-stressed adults, producing social avoidance at the highest dose tested, while younger animals displayed reduced sensitivity to this socially suppressing effect of U-62066. Interestingly, in stressed animals, the socially suppressing effects of the KOR agonist were blunted at all ages, with juveniles and adolescents exhibiting increased social preference in response to certain doses of U-62066. Taken together, these findings support the hypothesis that the DYN/KOR system changes with age and differentially responds and adapts to stress across development.

Effects of AMPA receptor antagonist, NBQX, and extrasynaptic GABAA agonist, THIP, on social behavior of adolescent and adult rats.

Adolescence is characterized by high significance of social interactions, along with a propensity to exhibit social facilitating effects of ethanol while being less sensitive than adults to the inhibition of social behavior that emerges at higher doses of ethanol. Among the neural characteristics of adolescence are generally enhanced levels of glutamatergic (especially NMDA receptor) activity relative to adults, whereas the GABA system is still developmentally immature. Activation of NMDA receptors likely plays a role in modulation of social behavior in adolescent animals as well as in socially facilitating and suppressing effects of ethanol. For instance, adolescent and adult rats differ in their sensitivities to the effects of NMDA antagonists and ethanol on social behavior, with adolescents but not adults demonstrating social facilitation at lower doses of both drugs and adults being more sensitive to the socially suppressing effects evident at higher doses of each. The roles of AMPA and extrasynaptic GABAA receptors in modulation of social behavior during adolescence and in adulthood are still unknown. The present study was designed to assess whether pharmacological blockade of AMPA receptors and/or activation of extrasynaptic GABAA receptors results in age-dependent alterations of social behavior. Adolescent and adult male and female Sprague-Dawley rats were injected with an assigned dose of either a selective AMPA antagonist, NBQX (Experiment 1) or extrasynaptic GABAA agonist, THIP (Experiment 2) and placed into a modified social interaction chamber for a 30-min habituation period prior to a 10-min social interaction test with a novel age- and sex-matched partner. Behaviors such as social investigation, contact behavior and play behavior were scored from video recordings of the interaction tests. In Experiment 1, NBQX produced similar social inhibition at higher doses in both age groups. In Experiment 2, THIP induced inhibition in adolescents, but not adults. No social facilitation was evident following low doses of either drug. Therefore, AMPA and extrasynaptic GABAA receptors appear to play little role if any in modulation of peer-directed social behavior in adolescence and adulthood and not likely to contribute to previously observed age differences in the social effects of acute ethanol.

Assessment of adolescent neurotoxicity: rationale and methodological considerations.

This introduction to the special issue of Neurotoxicology and Teratology on "Risk of neurobehavioral toxicity in adolescence" begins by broadly considering the ontogeny and phylogeny of adolescence, and the potential value of animal models of adolescence. Major findings from the emerging neuroscience of adolescence are then highlighted to establish the importance of studies of adolescent neurotoxicity. A variety of methodological issues that are of particular relevance to adolescent exposures are then discussed. These include consideration of pharmacokinetic factors, inclusion of other-aged comparison group(s), and issues involving timing, route of administration, and exposure-induced alterations in growth rate. Despite such methodological challenges, research to determine whether adolescence is a time of increased vulnerability (or greater resiliency) to specific drugs and environmental toxicants is progressing rapidly, as exemplified by the work presented in the articles of this special issue.

Effects of acute ethanol or amphetamine administration on the acoustic startle response and prepulse inhibition in adolescent and adult rats.

RATIONALE: Adolescents differ from adults in their sensitivity to a variety of psychoactive drugs. For example, adolescent rats are less sensitive to locomotor stimulant and stereotypic effects of amphetamine as well as to motor-impairing and hypnotic effects of ethanol while more sensitive to ethanol-induced disruption of brain plasticity. OBJECTIVE: The current study further explored age differences in psychopharmacological sensitivity by examining the effects of d-amphetamine (1.0 and 4.0 mg/kg) or ethanol (0.5, 1.0 and 1.5 g/kg) given interperitoneally on the acoustic startle response (ASR) and prepulse inhibition (PPI) in male adolescent and adult Sprague-Dawley rats. MATERIALS AND METHODS: The animals were given five startle trials (120 dB for 40 ms) before semi-randomized presentation of 12 startle trials interspersed with ten trials at each prepulse intensity (40 ms pulse of 5, 10, or 20 dB above background; 100 ms before the startle stimulus). RESULTS: Adolescent controls showed significantly less PPI than adults, replicating previous ontogenetic findings. The higher dose of amphetamine disrupted PPI in adult but not in adolescent animals, extending previous reports of an adolescent insensitivity to amphetamine to include this measure of sensorimotor gating. Ethanol exposure failed to alter PPI at either age, although both the 1.0 and 1.5 g/kg doses of ethanol significantly suppressed the magnitude of the ASR at both ages, potentially reflecting sedative or anxiolytic effects. CONCLUSION: These data provide further evidence of the relative insensitivity of adolescent animals to amphetamine, although no age effects were found in terms of ethanol sensitivity using these measures of startle and sensorimotor gating.

Consequences of adolescent use of alcohol and other drugs: Studies using rodent models.

Studies using animal models of adolescent exposure to alcohol, nicotine, cannabinoids, and the stimulants cocaine, 3,4-methylenedioxymethampethamine and methamphetamine have revealed a variety of persisting neural and behavioral consequences. Affected brain regions often include mesolimbic and prefrontal regions undergoing notable ontogenetic change during adolescence, although it is unclear whether this represents areas of specific vulnerability or particular scrutiny to date. Persisting alterations in forebrain systems critical for modulating reward, socioemotional processing and cognition have emerged, including apparent induction of a hyper-dopaminergic state with some drugs and/or attenuations in neurons expressing cholinergic markers. Disruptions in cognitive functions such as working memory, alterations in affect including increases in social anxiety, and mixed evidence for increases in later drug self-administration has also been reported. When consequences of adolescent and adult exposure were compared, adolescents were generally found to be more vulnerable to alcohol, nicotine, and cannabinoids, but generally not to stimulants. More work is needed to determine how adolescent drug exposure influences sculpting of the adolescent brain, and provide approaches to prevent/reverse these effects.

Adolescence. Alcohol sensitivity, tolerance, and intake.

Research conducted in laboratory animals has shown adolescents to be less sensitive to numerous ethanol effects that may serve as cues to limit intake, including effects evident during intoxication (e.g., ethanol-induced motor impairment, anxiolysis, social impairment, and sedation), as well as during the post-intoxication period (e.g., "hangover"-associated anxiogenesis). Conversely, adolescents are more sensitive than adults to a few ethanol effects, including ethanol-induced social facilitation and impairments in hippocampal long-term-potentiation. These age-specific ethanol sensitivities are not simply related to developmental differences in ethanol pharmacokinetics. Instead, they appear related in part to an ontogenetic decline in expression of within session (acute) tolerance and to differential rates of development of neural systems underlying different actions of ethanol. Relatively high levels of ethanol intake often seen in adolescent rodents and their human counterparts may be related not only to an attenuated sensitivity of adolescents to negative cues that normally serve to limit drinking, but also their greater sensitivity to both the facilitation of social behavior by ethanol and the stimulation of ethanol intake by social experiences. Although data are sparse, studies in laboratory animals hint that under some circumstances chronic adolescent exposure to ethanol may influence ongoing neural maturation and later neural, cognitive, and behavioral functioning, including later sensitivity to and propensity to use ethanol. Recommendations for further research are discussed.

Adolescent alcohol exposure: Are there separable vulnerable periods within adolescence?

There are two key alcohol use patterns among human adolescents that confer increased vulnerability for later alcohol abuse/dependence, along with neurocognitive alterations: (a) early initiation of use during adolescence, and (b) high rates of binge drinking that are particularly prevalent late in adolescence. The central thesis of this review is that lasting neurobehavioral outcomes of these two adolescent exposure patterns may differ. Although it is difficult to disentangle consequences of early use from later binge drinking in human studies given the substantial overlap between groups, these two types of problematic adolescent use are differentially heritable and hence separable to some extent. Although few studies using animal models have manipulated alcohol exposure age, those studies that have have typically observed timing-specific exposure effects, with more marked (or at least different patterns of) lasting consequences evident after exposures during early-mid adolescence than late-adolescence/emerging adulthood, and effects often restricted to male rats in those few instances where sex differences have been explored. As one example, adult male rats exposed to ethanol during early-mid adolescence (postnatal days [P] 25-45) were found to be socially anxious and to retain adolescent-typical ethanol-induced social facilitation into adulthood, effects that were not evident after exposure during late-adolescence/emerging adulthood (P45-65); exposure at the later interval, however, induced lasting tolerance to ethanol's social inhibitory effects that was not evident after exposure early in adolescence. Females, in contrast, were little influenced by ethanol exposure at either interval. Exposure timing effects have likewise been reported following social isolation as well as after repeated exposure to other drugs such as nicotine (and cannabinoids), with effects often, although not always, more pronounced in males where studied. Consistent with these timing-specific exposure effects, notable maturational changes in brain have been observed from early to late adolescence that could provide differential neural substrates for exposure timing-related consequences, with for instance exposure during early adolescence perhaps more likely to impact later self-administration and social/affective behaviors, whereas exposures later in adolescence may be more likely to influence cognitive tasks whose neural substrates (such as the prefrontal cortex [PFC]) are still undergoing maturation at that time. More work is needed, however to characterize timing-specific effects of adolescent ethanol exposures and their sex dependency, determine their neural substrates, and assess their comparability to and interactions with adolescent exposure to other drugs and stressors. Such information could prove critical for informing intervention/prevention strategies regarding the potential efficacy of efforts directed toward delaying onset of alcohol use versus toward reducing high levels of use and risks associated with that use later in adolescence.

Adolescent brain development and animal models.

Research examining brain development during adolescence is escalating rapidly along multiple dimensions, as illustrated by the remarkable diversity of trans-disciplinary work shown in this symposium. Ontogenetic transitions characteristics of adolescence are common among mammalian species. Although no other species demonstrates the full complexity of brain and behavioral function seen in human adolescents, adolescence appears to be a highly conserved developmental stage, its characteristics sculpted to meet common evolutionary pressures that include the avoidance of inbreeding at this time of sexual emergence. Numerous similarities are found between human adolescents and adolescents of other species in terms of developmental history and genetic constraints, as well as neurobehavioral and physiological characteristics. These similarities provide face and construct validity to support use of animal models as tools for the study of adolescence and the unique opportunities and vulnerabilities afforded by this developmental transition.

Adolescence and the trajectory of alcohol use: introduction to part VI.

Research in the area of adolescent alcohol use is progressing rapidly, as exemplified by the chapters in this section. Basic animal research in rodents has revealed adolescents to be more sensitive than adults to ethanol-induced disruptions in brain plasticity, although adolescents conversely are relatively insensitive to ethanol cues that serve to moderate intake. Risks for excessive alcohol consumption due to genetic background have been shown in primate research to be exacerbated by adverse early life experiences. Studies in clinical populations have revealed neurocognitive deficits evident years following adolescent alcohol abuse, along with evidence that some neural changes may predate adolescent alcohol abuse, whereas others appear to be a consequence of this abuse. Further research is needed to detail determinants and consequences of adolescent alcohol abuse and to identify potential protective factors to diminish the propensity for excessive use of alcohol during this critical developmental period.