Effects of adolescent alcohol consumption on the brain and behaviour.

Per occasion, alcohol consumption is higher in adolescents than in adults in both humans and laboratory animals, with changes in the adolescent brain probably contributing to this elevated drinking. This Review examines the contributors to and consequences of the use of alcohol in adolescents. Human adolescents with a history of alcohol use differ neurally and cognitively from other adolescents; some of these differences predate the commencement of alcohol consumption and serve as potential risk factors for later alcohol use, whereas others emerge from its use. The consequences of alcohol use in human adolescents include alterations in attention, verbal learning, visuospatial processing and memory, along with altered development of grey and white matter volumes and disrupted white matter integrity. The functional consequences of adolescent alcohol use emerging from studies of rodent models of adolescence include decreased cognitive flexibility, behavioural inefficiencies and elevations in anxiety, disinhibition, impulsivity and risk-taking. Rodent studies have also showed that adolescent alcohol use can impair neurogenesis, induce neuroinflammation and epigenetic alterations, and lead to the persistence of adolescent-like neurobehavioural phenotypes into adulthood. Although only a limited number of studies have examined comparable measures in humans and laboratory animals, the available data provide evidence for notable across-species similarities in the neural consequences of adolescent alcohol exposure, providing support for further translational efforts in this context.

Author Correction: Effects of adolescent alcohol consumption on the brain and behaviour.

In the initially published version of this article, the following sentence was incorrect: "Studies that have compared equivalent exposures to alcohol in adolescent and adult animals have found that the effects of alcohol exposure during adolescence are generally not evident or are less pronounced than after comparable alcohol exposure in adulthood". The sentence should have read: "Studies that have compared equivalent exposures to alcohol in adolescent and adult animals have found that the effects of alcohol exposure during adulthood are generally not evident or are less pronounced than after comparable alcohol exposure in adolescence". The sentence has been corrected in the HTML and PDF versions of the article.

Impact of adolescent intermittent ethanol exposure in male and female rats on social drinking and neuropeptide gene expression.

BACKGROUND: Alcohol use during adolescence can alter maturational changes that occur in brain regions associated with social and emotional responding. Our previous studies have shown that adult male, but not female rats demonstrate social anxiety-like alterations and enhanced sensitivity to ethanol-induced social facilitation following adolescent intermittent ethanol exposure (AIE). These consequences of AIE may influence adult social drinking in a sex-specific manner. METHODS: To test the effects of AIE on social drinking, male and female Sprague-Dawley rats exposed to water or ethanol (0 or 4 g/kg, intragastrically, every other day, between postnatal day [P] 25 and 45) were tested as adults (P72-83) in a social drinking paradigm (30-minute access to a 10% ethanol solution in supersac or supersac alone in groups of three same-sex littermates across two 4-day cycles separated by 4 days off). Social behavior was assessed during the last drinking session, along with assessment of oxytocin (OXT), oxytocin receptor (OXTR), vasopressin (AVP), and vasopressin receptors 1a and 1b (AVPR1a, AVPR1b) in the hypothalamus and lateral septum. RESULTS: Males exposed to AIE consumed more ethanol than water-exposed controls during the second drinking cycle, whereas AIE did not affect supersac intake in males. AIE-exposed females consumed less ethanol and more supersac than water-exposed controls. Water-exposed females drinking ethanol showed more social investigation and significantly higher hypothalamic OXTR, AVP, and AVPR1b gene expression than their counterparts ingesting supersac and AIE females drinking ethanol. In males, hypothalamic AVPR1b gene expression was affected by drinking solution, with significantly higher expression evident in males drinking ethanol than those consuming supersac. CONCLUSIONS: Collectively, these findings provide new evidence regarding sex-specific effects of AIE on social drinking and suggest that the hypothalamic OXT and AVP systems are implicated in the effects of ingested ethanol on social behavior in a sex- and adolescent-exposure-dependent manner.

Adolescent intermittent ethanol exposure does not alter responsiveness to ifenprodil or expression of vesicular GABA and glutamate transporters.

Adolescent intermittent ethanol (AIE) exposure in the rat results in a retention of adolescent-like responsiveness to ethanol into adulthood characterized by enhanced sensitivity to socially facilitating and decreased sensitivity to socially suppressing and aversive effects. Similar pattern of responsiveness to social and aversive effects of the selective glutamate NMDA NR2B receptor antagonist ifenprodil is evident in adolescent rats, suggesting that AIE would also retain this pattern of ifenprodil sensitivity into adulthood. Social (Experiment 1) and aversive (measured via conditioned taste aversion; Experiment 2) effects of ifenprodil were assessed in adult male and female rats following AIE exposure. Sensitivity to the social and aversive effects of ifenprodil was not affected by AIE exposure. Experiment 3 assessed protein expression of vesicular transporters of GABA (vGAT) and glutamate (vGlut2) within the prelimbic cortex and nucleus accumbens in adolescents versus adults and in AIE adults versus controls. vGlut2 expression was higher in adolescents relative to adults within the PrL, but lower in the NAc. AIE adults did not retain these adolescent-typical ratios. These findings suggest that AIE is not associated with the retention of adolescent-typical sensitivity to NR2B receptor antagonism, along with no AIE-induced shift in vGlut2 to vGAT ratios.

General Anesthetic Exposure During Early Adolescence Persistently Alters Ethanol Responses.

BACKGROUND: Adolescent alcohol abuse can lead to behavioral dysfunction and chronic, relapsing alcohol use disorder (AUD) in adulthood. However, not all adolescents that consume alcohol will develop an AUD; therefore, it is critical to identify neural and environmental risk factors that contribute to increases in susceptibility to AUDs following adolescent alcohol (ethanol [EtOH]) exposure. We previously found that adolescent anesthetic exposure led to strikingly similar behavioral and neural effects as adolescent alcohol exposure. Therefore, we tested the hypothesis that general anesthetic exposure during early adolescence would alter EtOH responses consistent with an exacerbation of the adolescent alcohol phenotype. METHODS: To test this hypothesis, early-adolescent male Sprague-Dawley rats were exposed for a short duration to the general anesthetic isoflurane and tested on multiple EtOH-induced behaviors in mid-late adolescence or adulthood. RESULTS: Adolescent rats exposed to isoflurane exhibited decreases in sensitivity to negative properties of EtOH such as its aversive, hypnotic, and socially suppressive effects, as well as increases in voluntary EtOH intake and cognitive impairment. Select behaviors were noted to persist into adulthood following adolescent isoflurane exposure. Similar exposure in adults had no effects on EtOH sensitivity. CONCLUSIONS: This study demonstrates for the first time that early-adolescent isoflurane exposure alters EtOH sensitivity in a manner consistent with an exacerbation of adolescent-typical alcohol responding. These findings suggest that general anesthetic exposure during adolescence may be an environmental risk factor contributing to an enhanced susceptibility to developing AUDs in an already vulnerable population.

Mechanisms of Persistent Neurobiological Changes Following Adolescent Alcohol Exposure: NADIA Consortium Findings.

The Neurobiology of Adolescent Drinking in Adulthood (NADIA) Consortium has focused on the impact of adolescent binge drinking on brain development, particularly on effects that persist into adulthood. Adolescent binge drinking is common, and while many factors contribute to human brain development and alcohol use during adolescence, animal models are critical for understanding the specific consequences of alcohol exposure during this developmental period and the underlying mechanisms. Using adolescent intermittent ethanol (AIE) exposure models, NADIA investigators identified long-lasting AIE-induced changes in adult behavior that are consistent with observations in humans, such as increased alcohol drinking, increased anxiety (particularly social anxiety), increased impulsivity, reduced behavioral flexibility, impaired memory, disrupted sleep, and altered responses to alcohol. These behavioral changes are associated with multiple molecular, cellular, and physiological alterations in the brain that persist long after AIE exposure. At the molecular level, AIE results in long-lasting changes in neuroimmune/trophic factor balance and epigenetic-microRNA (miRNA) signaling across glia and neurons. At the cellular level, AIE history is associated in adulthood with reduced expression of cholinergic, serotonergic, and dopaminergic neuron markers, attenuated cortical thickness, decreased neurogenesis, and altered dendritic spine and glial morphology. This constellation of molecular and cellular adaptations to AIE likely contributes to observed alterations in neurophysiology, measured by synaptic physiology, EEG patterns, and functional connectivity. Many of these AIE-induced brain changes replicate findings seen in postmortem brains of humans with alcohol use disorder (AUD). NADIA researchers are now elucidating mechanisms of these adaptations. Emerging data demonstrate that exercise, antiinflammatory drugs, anticholinesterases, histone deacetylase inhibitors, and other pharmacological compounds are able to prevent (administered during AIE) and/or reverse (given after AIE) AIE-induced pathology in adulthood. These studies support hypotheses that adolescent binge drinking increases risk of adult hazardous drinking and influences brain development, and may provide insight into novel therapeutic targets for AIE-induced neuropathology and AUDs.

Excitatory/inhibitory balance across ontogeny contributes to age-specific behavioral outcomes of ethanol-like challenge in conditioned taste aversion.

Adolescent-typical sensitivities to ethanol (EtOH) are characterized in part by reduced sensitivity to EtOH's aversive effects. Rodent studies have shown that adolescents are less sensitive than adults to aversive properties of EtOH in a conditioned taste aversion (CTA) paradigm. To the extent that EtOH exerts antagonist-like actions upon glutamate receptors and/or agonist-like actions upon γ-aminobutyric acid (GABA) receptors, age differences in excitatory/inhibitory balance may regulate age-specific EtOH sensitivities, such as attenuated sensitivity of adolescents to EtOH aversion. In our experiments, adolescent and adult Sprague-Dawley rats were tested for CTA following challenge with one of the following pharmacological agents: glutamatergic AMPA1 receptor antagonist NBQX, glutamatergic N-methyl-d-aspartate NR2B receptor antagonist ifenprodil, and extrasynaptic GABAA receptor agonist THIP to determine whether these induced age-specific aversive sensitivities like those seen with EtOH. NBQX administration did not induce CTA. The highest dose of extrasynaptic GABAA agonist THIP induced CTA in adolescents but not adults, an opposite ontogenetic profile as seen following EtOH. Ifenprodil exerted an age-specific pattern of CTA similar to that seen with EtOH in males, with adolescents being insensitive to ifenprodil's aversive effects relative to adults. Thus, only antagonism of NR2B receptors in male rats mimicked age-specific sensitivities to the aversive effects of EtOH.

Age differences in conditioned place preferences and taste aversions to nicotine.

Adolescents and adults differ in their behavioral sensitivities to drugs of abuse, including nicotine. Studies have shown that both rewarding and aversive properties of drugs of abuse can exist concomitantly. The present study investigated the ontogeny of these opposing qualities across a range of doses using a combined conditioned taste aversion and place preference paradigm in pair-housed rats that were not deprived of food or water. Results indicated that adolescents were more sensitive to the rewarding properties of nicotine than adults. In contrast, although all doses produced a taste aversion at both ages in the same rats, the aversion was weaker at lower than high doses in adolescents whereas adults showed strong aversion at all doses, suggesting modest attenuation in nicotine's aversive properties among adolescents relative to adults. Thus, attenuated aversive and accented appetitive sensitivities of adolescents to nicotine can be experienced simultaneously in the same animals. © 2016 Wiley Periodicals, Inc. Dev Psychobiol 58: 660-666, 2016.

Ethanol intake under social circumstances or alone in sprague-dawley rats: impact of age, sex, social activity, and social anxiety-like behavior.

BACKGROUND: In human adolescents, heavy drinking is often predicted by high sociability in males and high social anxiety in females. This study assessed the impact of baseline levels of social activity and social anxiety-like behavior in group-housed adolescent and adult male and female Sprague-Dawley rats on ethanol (EtOH) intake when drinking alone or in a social group. METHODS: Social activity and anxiety-like behavior initially were assessed in a modified social interaction test, followed by 6 drinking sessions that occurred every other day in animals given ad libitum food and water. Sessions consisted of 30-minute access to 10% EtOH in a "supersac" (3% sucrose + 0.1% saccharin) solution given alone as well as in groups of 5 same-sex littermates, with order of the alternating session types counterbalanced across animals. RESULTS: Adolescent males and adults of both sexes overall consumed more EtOH under social than alone circumstances, whereas adolescent females ingested more EtOH when alone. Highly socially active adolescent males demonstrated elevated levels of EtOH intake relative to their low and medium socially active counterparts when drinking in groups, but not when tested alone. Adolescent females with high levels of social anxiety-like behavior demonstrated the highest EtOH intake under social, but not alone circumstances. Among adults, baseline levels of social anxiety-like behavior did not contribute to individual differences in EtOH intake in either sex. CONCLUSIONS: The results clearly demonstrate that in adolescent rats, but not their adult counterparts, responsiveness to a social peer predicts EtOH intake in a social setting-circumstances under which drinking typically occurs in human adolescents. High levels of social activity in males and high levels of social anxiety-like behavior in females were associated with elevated social drinking, suggesting that males ingest EtOH for its socially enhancing properties, whereas females ingest EtOH for its socially anxiolytic effects.

Persistent loss of hippocampal neurogenesis and increased cell death following adolescent, but not adult, chronic ethanol exposure.

Although adolescence is a common age to initiate alcohol consumption, the long-term consequences of exposure to alcohol at this time of considerable brain maturation are largely unknown. In studies utilizing rodents, behavioral evidence is beginning to emerge suggesting that the hippocampus may be persistently affected by repeated ethanol exposure during adolescence, but not by comparable alcohol exposure in adulthood. The purpose of this series of experiments was to explore a potential mechanism of hippocampal dysfunction in adults exposed to ethanol during adolescence. Given that disruption in adult neurogenesis has been reported to impair performance on tasks thought to be hippocampally related, we used immunohistochemistry to assess levels of doublecortin (DCX), an endogenous marker of immature neurons, in the dentate gyrus (DG) of the hippocampus 3-4 weeks after adolescent (postnatal day, PD28-48) or adult (PD70-90) intermittent ethanol exposure to 4 g/kg ethanol administered intragastrically. We also investigated another neurogenic niche, the subventricular zone (SVZ), to determine if the effects of ethanol exposure were region specific. Levels of cell proliferation and cell death were also examined in the DG via assessing Ki67 and cleaved caspase-3 immunoreactivity, respectively. Significantly less DCX was observed in the DG of adolescent (but not adult) ethanol-exposed animals about 4 weeks after exposure when these animals were compared to control age-mates. The effects of adolescent ethanol on DCX immunoreactivity were specific to the hippocampus, with no significant exposure effects emerging in the SVZ. In both the DG and the SVZ there was a significant age-related decline in neurogenesis as indexed by DCX. The persistent effect of adolescent ethanol exposure on reduced DCX in the DG appears to be related to significant increases in cell death, with significantly more cleaved caspase-3-positive immunoreactivity observed in the adolescent ethanol group compared to controls, but no alterations in cell proliferation when indexed by Ki67. These results suggest that a history of adolescent ethanol exposure results in lowered levels of differentiating neurons, probably due at least in part to increased cell death of immature neurons. These effects were evident in adulthood, weeks following termination of the chronic exposure, and may contribute to previously reported behavioral deficits on hippocampal-related tasks after chronic ethanol exposure in adolescence.

Pre-pubertal gonadectomy and the social consequences of acute ethanol in adolescent male and female rats.

It has previously been shown that pre-pubertal or adult gonadectomy (GX) increases ethanol intake in male rats. This study examined whether this sex-selective increase reflects a GX-induced maintenance in males of more adolescent-typical responsiveness to ethanol characterized by enhanced sensitivity to positive (e.g., socially facilitating) and a decreased sensitivity to adverse (e.g., socially inhibitory) effects of ethanol. Male and female Sprague-Dawley rats were pre-pubertally GX, sham (SH)-operated, or non-manipulated (NM) at postnatal day (P) 25. During the late adolescent transition into adulthood (P48 - baseline day), rats were given a saline injection, placed alone into a familiar test apparatus for 30min and then exposed for 10min to an unfamiliar partner of the same age and sex. On the following day (P49), similar testing occurred after administration of 0.5, 0.75, 1.0 or 1.25g/kg ethanol. At baseline, GX males and females displayed higher levels of social activity (especially adolescent-typical play and contact behavior) than SH and NM animals, with GX females displaying greater social activity than GX males. Neither males nor females demonstrated social facilitation at lower ethanol doses, regardless of hormonal status. Whereas the social inhibitory effects of higher doses of ethanol were similar across groups among females, SH males were less sensitive than both GX and NM males to ethanol-induced social inhibition. These results suggest that enhanced ethanol intake in GX males is not related to alterations in sensitivity to ethanol's social inhibitory effects. GX, however, results in retention of adolescent-typical social behaviors, with older GX adolescent rats resembling early adolescents in exhibiting elevated social activity-particularly play and contact behavior.

Consequences of adolescent or adult ethanol exposure on tone and context fear retention: effects of an acute ethanol challenge during conditioning.

BACKGROUND: An acute ethanol (EtOH) challenge prior to fear conditioning typically disrupts fear retention to contextual cues to a greater degree than fear retention to a discrete tone cue, and adolescent rats are less sensitive than adults to these EtOH-induced disruptions of context fear memory. Given that some research suggests that repeated EtOH exposure during adolescence may "lock-in" adolescent-typical EtOH sensitivity into adulthood, the purpose of this study was to determine whether adults exposed to EtOH as adolescents would be less sensitive to EtOH-induced disruptions of context fear. METHODS: Male Sprague-Dawley rats were given 4 g/kg intragastric EtOH (25% v/v) or water every 48 hours for a total of 11 exposures during adolescence (postnatal day [P] 28 to 48) or adulthood (P70-90). After a 22-day non-EtOH period, animals were acutely challenged with 1 g/kg intraperitoneal EtOH or saline 10 minutes prior to tone or context (noncued) fear conditioning. Tone and context fear retention was subsequently examined. RESULTS: Regardless of age or exposure history, typical deficits in context fear retention were evident after EtOH challenge during conditioning. Similarly, tone fear retention was disrupted in all animals that were trained in the presence of EtOH, which was somewhat surprising given the relative resistance of tone fear retention to an acute EtOH challenge. CONCLUSIONS: These results do not support the notion of a "lock-in" of adolescent-typical EtOH sensitivity as there was no influence of exposure age on sensitivity to the disruptive effects of an acute EtOH challenge. Thus, it appears that not all adolescent-like EtOH sensitivities persist into adulthood after prior EtOH exposure during adolescence.

Age differences in ethanol discrimination: acquisition and ethanol dose generalization curves following multiple training conditions in adolescent and adult rats.

BACKGROUND: Adolescents and adults vary in sensitivity to many effects of ethanol (EtOH), although it is unknown whether they also differ in their perception of EtOH's subjective cues. This study characterized EtOH discrimination in adolescent and adult male rats using a rapidly acquired Pavlovian conditioned approach procedure. METHODS: EtOH at 1 of the 3 training doses (0.75, 1.0, or 1.25 g/kg) served as either a positive (POS) or negative (NOS) occasion setter. Each 20-minute training session consisted of eight 15-second presentations of 2 cue lights located on either side of a dipper delivering chocolate Boost(®) . For POS-trained rats, the cue lights reliably predicted 5-second presentations of chocolate Boost during EtOH but not saline sessions, with the opposite contingencies used for NOS-trained rats. Anticipatory approach behavior (head entries into the reward delivery area) in the presence and absence of the cue lights was used to calculate discrimination scores on EtOH and saline sessions. Following acquisition, various doses of EtOH (0 to 1.5 g/kg) were administered to establish generalization curves. RESULTS: Although animals of both ages responded differentially on EtOH and saline sessions by the end of acquisition, adults met criterion more quickly and had higher discrimination scores during reinforced sessions than adolescents. Whereas adolescents failed to demonstrate any dose-dependent responding during testing when trained with the 0.75 or 1.25 g/kg EtOH doses, adults demonstrated broader EtOH generalization during testing sessions following training with all 3 EtOH doses. Among adolescents trained with 1.0 g/kg EtOH, less generalization occurred relative to adults. CONCLUSIONS: Adolescents were less sensitive to EtOH's interoceptive effects, indicating that EtOH is likely a more salient cue for adults than for adolescents. These findings contribute to evidence that suggests adolescent-typical insensitivity to internal cues that typically limit EtOH consumption may contribute to the elevated intake commonly reported during this developmental period.

Ethanol reduces evoked dopamine release and slows clearance in the rat medial prefrontal cortex.

BACKGROUND: Ethanol (EtOH) intoxication affects cognitive performance, contributing to attentional deficits and poor decision making, which may occur via actions in the medial prefrontal cortex (mPFC). mPFC function is modulated by the catecholamines dopamine and norepinephrine. In this study, we examine the acute effects of EtOH on electrically evoked dopamine release and clearance in the mPFC of anesthetized rats naïve to alcohol or chronically exposed to alcohol during adolescence. METHODS: Dopamine release and clearance was evoked by electrical stimulation of the ventral tegmental area (VTA) and measured in the mPFC of anesthetized rats with fast-scan cyclic voltammetry. In Experiments 1 and 2, effects of a high dose of EtOH (4 g/kg, intraperitoneally) on dopamine neurotransmission in the mPFC of EtOH-naïve rats and rats given EtOH exposure during adolescence were investigated. Effects of cumulative dosing of EtOH (0.5 to 4 g/kg) on the dopamine release and clearance were investigated in Experiment 3. Experiment 4 studied effects of EtOH locally applied to the VTA on the dopamine neurotransmission in the mPFC of EtOH-naïve rats. RESULTS: A high dose of EtOH decreased evoked dopamine release within 10 minutes of administration in EtOH-naïve rats. When tested via cumulative dosing from 0.5 to 4 g/kg, both 2 and 4 g/kg EtOH inhibited evoked dopamine release in the mPFC of EtOH-naïve rats, while 4 g/kg EtOH also slowed dopamine clearance. A similar effect on electrically evoked dopamine release in the mPFC was observed after infusion of EtOH into the VTA. Interestingly, intermittent EtOH exposure during adolescence had no effect on observed changes in mPFC dopamine release and clearance induced by acute EtOH administration. CONCLUSIONS: Taken together, these data describe EtOH-induced reductions in the dynamics of VTA-evoked mPFC dopamine release and clearance, with the VTA contributing to the attenuation of evoked mPFC dopamine release induced by EtOH.

Are we drunk yet? Motor versus cognitive cues of subjective intoxication.

BACKGROUND: Perception of alcohol intoxication presumably plays an important role in guiding behavior during a current drinking episode. Yet, there has been surprisingly little investigation of what aspects associated with intoxication are used by individuals to attribute their level of intoxication. METHODS: Building on recent laboratory-based findings, this study employed a complex field-based design to explore the relative contributions of motor performance versus cognitive performance-specifically executive control-on self-attributions of intoxication. Individuals recruited outside of bars (N = 280; mean age = 22; range: 18 to 32) completed a structured interview, self-report questionnaire, and neuropsychological testing battery, and provided a breath alcohol concentration (BrAC) sample. RESULTS: Results of a multiple linear regression analysis demonstrated that current level of subjective intoxication was associated with current alcohol-related stimulant effects, current sedative effects, and current BrAC. After controlling for the unique variance accounted for by these factors, subjective intoxication was better predicted by simple motor speed, as indexed by performance on the Finger Tapping Test, than by executive control, as indexed by performance on the Trail Making Test. CONCLUSIONS: These results-generated from data collected in a naturally occurring setting-support previous findings from a more traditional laboratory-based investigation, thus illustrating the iterative process of linking field methodology and controlled laboratory experimentation.

Effects of ethanol on social approach and 50 kHz ultrasonic vocalization production in adolescent male Sprague-Dawley rats.

Low doses of ethanol have been shown to facilitate social behavior in adolescent rats. The present study sought to investigate whether this ethanol effect is associated with increases in the incentive salience of social stimuli when assessed via approach behavior toward a peer (separated from the experimental animal by a mesh barrier) and 50 kHz ultrasonic vocalization (USV) production in that context. A 0.5 g/kg ethanol dose was found to increase social approach/investigation of adolescent male Sprague-Dawley rats during the first 5 min of the 10 min test whereas 50 kHz USV production was elevated by 0.25 g/kg during the last 5 min of testing. 50 kHz USV production and social approach were generally not correlated, indicating a clear dissociation between these measures. This is the first study to demonstrate that ethanol-induced social facilitation in adolescents is associated with an ethanol-induced increase in the incentive salience of social stimuli.

Tone conditioning potentiates rather than overshadows context fear in adult animals following adolescent ethanol exposure.

We have shown that adults exposed to ethanol during adolescence exhibit a deficit in the retention of context fear, reminiscent of that normally seen in preweanling rats. However, preweanlings have been reported to exhibit a potentiation of context fear when they are conditioned in the presence of a tone. Therefore, this study examined context retention 24 hr after tone or context conditioning in male Sprague-Dawley rats exposed intragastrically to 4 g/kg ethanol or water every 48 hr (total of 11 exposures) during adolescence [Postnatal day (P) 28-48] or adulthood (P70-90). Approximately 3 weeks following exposure, retention of fear to the context in animals exposed to ethanol during adolescence was attenuated after context conditioning, but enhanced after tone conditioning. Comparable adult ethanol exposure groups showed typical overshadowing of context fear retention after tone conditioning. These data suggest that adolescent ethanol exposure may induce an immature pattern of cognitive processing.

Effects of the kappa opioid receptor antagonist, nor-binaltorphimine, on ethanol intake: impact of age and sex.

The kappa opioid receptor (KOR) antagonist, nor-binaltorphimine (nor-BNI), was used to investigate the role of the KOR system in mediating ethanol intake. On P25 (adolescent) or P67 (adult) male and female rats were individually housed and given ad libitum access to food and water. The experimental procedure was initiated on P28 or P70: animals were given 30 min/day access to a 10% ethanol/supersaccharin solution every other day (3 baseline exposures). On the day after the final baseline test, rats were injected with nor-BNI (0, 2.5, 5, 10 mg/kg), with testing initiated 24 hr later (30-min access every other day, 3 test exposures). Nor-BNI (10 mg/kg) increased ethanol intake in adult males, whereas the same dose decreased intake in adult females, suggesting pronounced sex differences in KOR-associated mediation of ethanol intake in adulthood. There was no impact of nor-BNI in adolescent animals of either sex, suggesting that the KOR may play less of a role in modulating ethanol intake during adolescence.

Puberty and gonadal hormones: role in adolescent-typical behavioral alterations.

This article is part of a Special Issue "Puberty and Adolescence". Adolescence is characterized by a variety of behavioral alterations, including elevations in novelty-seeking and experimentation with alcohol and other drugs of abuse. Some adolescent-typical neurobehavioral alterations may depend upon pubertal rises in gonadal hormones, whereas others may be unrelated to puberty. Using a variety of approaches, studies in laboratory animals have not revealed clear relationships between pubertal-related changes and adolescent- or adult-typical behaviors that are not strongly sexually dimorphic. Data reviewed suggest surprisingly modest influences of gonadal hormones on alcohol intake, alcohol preference and novelty-directed behaviors. Gonadectomy in males (but not females) increased ethanol intake in adulthood following surgery either pre-pubertally or in adulthood, with these increases in intake largely reversed by testosterone replacement in adulthood, supporting an activational role of androgens in moderating ethanol intake in males. In contrast, neither pre-pubertal nor adult gonadectomy influenced sensitivity to the social inhibitory or aversive effects of ethanol when indexed via conditioned taste aversions, although gonadectomy at either age altered the microstructure of social behavior of both males and females. Unexpectedly, the pre-pubertal surgical manipulation process itself was found to increase later ethanol intake, decrease sensitivity to ethanol's social inhibitory effects, attenuate novelty-directed behavior and lower social motivation, with gonadal hormones being necessary for these long-lasting effects of early surgical perturbations.

Effects of voluntary access to sweetened ethanol during adolescence on intake in adulthood.

BACKGROUND: The prevalence of alcohol use during adolescence is concerning given that early age of alcohol initiation is correlated with the development of alcohol-related problems later in life. The purpose of this series of studies was to assess whether voluntary ethanol (EtOH) exposure during adolescence would influence EtOH drinking behavior in adulthood using an animal model. METHODS: Pair-housed Sprague-Dawley adolescent (postnatal day [P] 28 to 42) rats of both sexes were given single bottle access to 1 of 3 solutions in their home cages-10% EtOH in "supersac" (0.125% saccharin and 3% sucrose) (EtOH/SS), supersac without EtOH (SS), or water-for 30 minutes every other day for a total of 8 drinking days or were left nonmanipulated (NM). Animals were NM thereafter until adulthood (P70) at which time they were given 1-bottle, 30 minute limited access tests with 20% EtOH every other day (Exp 1), 10% EtOH in SS (Exp 2), or SS without EtOH (Exp 3). RESULTS: Adolescent EtOH/SS exposure increased adulthood consumption of EtOH/SS (Exp 2), but not 20% unsweetened EtOH (Exp 1) or SS (Exp 3), with this increase most pronounced at the beginning of the 8 intake day procedure. Access to SS (without EtOH) during adolescence produced an analogous effect, with increased adult SS consumption during the first 2 intake days, but no increases in either of the EtOH test solutions. CONCLUSIONS: Solution-specific increases in adulthood intake after adolescent exposure are most likely associated with solution acceptance due to familiarity. This is an important consideration for future intake studies assessing the influence of EtOH exposure during adolescence on intake of EtOH in adulthood.