Showing papers in "Alcoholism: Clinical and Experimental Research in 2010"

Genome-wide association study of alcohol dependence implicates a region on chromosome 11

Abstract: Background: Alcohol dependence is a complex disease, and although linkage and candidate gene studies have identified several genes associated with the risk for alcoholism, these explain only a portion of the risk.

Behavioral and Biological Indicators of Impulsivity in the Development of Alcohol Use, Problems, and Disorders

Abstract: Alcohol use disorders (AUDs) are a devastating public health problem. The construct of impulsivity is biologically based and heritable, and its various dimensions are relevant for understanding alcohol use. The goal of the current manuscript is to review recent behavioral and biological research examining various dimensions of impulsivity and their relation to AUDs from risk for initial use through dependence and relapse. Moreover, we also highlight key psychological variables including affective processes as they relate to current use and early indications of alcohol problems, as well as psychopathology, violence, and aggression in relation to AUDs. Each section includes a critical summary and we conclude the review with future directions focused on issues relevant to measurement, causality, and intervention. Throughout the review, we attempt to be as specific as possible about the dimensions of impulsivity being referenced, while attempting to draw parallels and highlighting differences as the existing literature allows.

Efficacy and Safety of Baclofen for Alcohol Dependence: A Randomized, Double-Blind, Placebo-Controlled Trial

Abstract: Background: Recent clinical trials and case-reports indicate that baclofen, a GABAB agonist, may have efficacy for alcohol dependence Baclofen has been shown to enhance abstinence, to reduce drinking quantity, to reduce craving, and to reduce anxiety in alcohol-dependent individuals in 2 placebo-controlled trials in Italy However, the clinical trial data with baclofen is limited The purpose of the present study was to test the efficacy and tolerability of baclofen in alcohol dependence in the United States Methods: The study was a double-blind, placebo-controlled, randomized study comparing 30 mg/d of baclofen to placebo over 12 weeks of treatment and utilizing 8 sessions of BRENDA, a low-intensity psychosocial intervention One hundred and twenty-one subjects were screened to yield 80 randomized subjects (44 men) with randomization balanced for gender Percent heavy drinking days was the primary outcome measure with other drinking outcomes, anxiety levels, and craving as secondary outcomes Tolerability was examined Results: Seventy-six percent of subjects completed the study No difference by drug condition was seen in percentage of heavy drinking days where on-average rates were 255% (±236%) for placebo and 259% (±232%) for baclofen during treatment (t73 = 059, p = 056) Similarly, no differences were seen by drug condition in percentage of days abstinent, time to first drink, or time to relapse to heavy drinking Baclofen was associated with a significant reduction in state anxiety (F1,73 = 539, p = 002) Baclofen was well tolerated with only 2 individuals stopping baclofen because of adverse events There were no serious adverse events Conclusions: Baclofen, a GABAB agonist, represents a possible new pharmacotherapeutic approach to alcohol dependence Despite encouraging preclinical data and prior positive clinical trials with baclofen in Italy, the current trial did not find evidence that baclofen is superior to placebo in the treatment of alcohol dependence Additional clinical trial work is necessary to establish whether baclofen does or does not have therapeutic efficacy in alcohol dependence and, if it does, what factors are predictive of response

Acute Alcohol Effects on Inhibitory Control and Implicit Cognition: Implications for Loss of Control Over Drinking

Abstract: Alcohol impairs inhibitory control, and it alters implicit alcohol cognitions including attentional bias and implicit associations. These effects are seen after doses of alcohol which do not lead to global impairments in cognitive performance. We review studies which demonstrate that the effects of alcohol on inhibitory control are associated with the ability of alcohol to prime alcohol-seeking behavior. We also hypothesize that alcohol-induced changes in implicit alcohol cognitions may partially mediate alcohol-induced priming of the motivation to drink. Based on contemporary theoretical models and conceptualizations of executive function, impulsivity, and the motivational salience of alcohol-related cues, we speculate on other aspects of cognition that may underlie alcohol’s effects on alcohol seeking. Inconsistencies in existing research and priorities for future research are highlighted, including dose effects and the potential interactions between chronic heavy drinking and the acute effects of alcohol on these cognitive processes.

Changes in sensation seeking and risk-taking propensity predict increases in alcohol use among early adolescents

Abstract: Background: Conceptual models implicating disinhibitory traits often are applied to understanding emergent alcohol use, but, little is known of how inter-individual changes in these constructs relate to increases in alcohol use in early adolescence. The current study utilized behavioral and self-report instruments to capture the disinhibitory-based constructs of sensation seeking and risk-taking propensity to examine if increases in these constructs over time related to increases in early adolescent alcohol use. Methods: Participants included a community sample of 257 early adolescents (aged 9 to 12) who completed a self-report measure of sensation seeking, a behavioral task assessing risk-taking propensity, and a self-report of past year alcohol use, at 3 annual assessment waves. Results: Both sensation seeking and risk-taking propensity demonstrated significant increases over time, with additional evidence that change in the behavioral measure of risk-taking propensity was not because of practice effects. Greater sensation seeking and greater risk-taking propensity demonstrated concurrent relationships with past year alcohol use at each assessment wave. Prospective analyses indicated that after accounting for initial levels of alcohol use, sensation seeking, and risk-taking propensity at the first assessment wave, larger increases in both constructs predicted greater odds of alcohol use at subsequent assessment waves. Conclusions: Results indicate the role of individual changes in disinhibitory traits in initial alcohol use in early adolescents. Specifically, findings suggest it is not simply initial levels of sensation seeking and risk-taking propensity that contribute to subsequent alcohol use but in particular increases in each of these constructs that predict greater odds of use. Future work should continue to assess the development of sensation seeking and risk-taking propensity in early adolescence and target these constructs in interventions as a potential means to reduce adolescent alcohol use. Language: en

Insight Into the Relationship Between Impulsivity and Substance Abuse From Studies Using Animal Models

Abstract: Drug use disorders are often accompanied by deficits in the capacity to efficiently process reward-related information and to monitor, suppress, or override reward-controlled behavior when goals are in conflict with aversive or immediate outcomes. This emerging deficit in behavioral flexibility and impulse control may be a central component of the progression to addiction, as behavior becomes increasingly driven by drugs and drug-associated cues at the expense of more advantageous activities. Understanding how neural mechanisms implicated in impulse control are affected by addictive drugs may therefore prove a useful strategy in the search for new treatment options. Animal models of impulsivity and addiction could make a significant contribution to this endeavor. Here, some of the more common behavioral paradigms used to measure different aspects of impulsivity across species are outlined, and the importance of the response to reward-paired cues in such paradigms is discussed. Naturally occurring differences in forms of impulsivity have been found to be predictive of future drug self-administration, but drug exposure can also increase impulsive responding. Such data are in keeping with the suggestion that impulsivity may contribute to multiple stages within the spiral of addiction. From a neurobiological perspective, converging evidence from rat, monkey, and human studies suggest that compromised functioning within the orbitofrontal cortex may critically contribute to the cognitive sequelae of drug abuse. Changes in gene transcription and protein expression within this region may provide insight into the mechanism underlying drug-induced cortical hypofunction, reflecting new molecular targets for the treatment of uncontrolled drug-seeking and drug-taking behavior.

Is the full version of the AUDIT really necessary? Study of the validity and internal construct of its abbreviated versions

Abstract: Background: This study was aimed at assessing the psychometric qualities of the abbreviated versions of the Alcohol Use Disorders Identification Test (AUDIT-3, AUDIT-4, AUDIT-C, AUDIT-PC, AUDIT-QF, FAST, and Five-Shot) and at comparing them to the 10-item AUDIT and the CAGE in 2 samples of Brazilian adults. Methods: The validity and internal consistency of the scales were assessed in a sample of 530 subjects attended at an emergency department and at a Psychosocial Care Center for Alcohol and Drugs. The Structured Clinical Interview for DSM-IV was used as the diagnostic comparative measure for the predictive validity assessment. The concurrent validity between the scales was analyzed by means of Pearson’s correlation coefficient. Results: The assessment of the predictive validity of the abbreviated versions showed high sensitivity (of 0.78 to 0.96) and specificity (of 0.74 to 0.94) indices, with areas under the curve as elevated as those of the AUDIT (0.89 and 0.92 to screen for abuse and 0.93 and 0.95 in the screening of dependence). The CAGE presented lower indices: 0.81 for abuse and 0.87 for dependence. The analysis of the internal consistency of the AUDIT and its versions exhibited Cronbach’s alpha coefficients between 0.83 and 0.94, while the coefficient for the CAGE was 0.78. Significant correlations were found between the 10-item AUDIT and its versions, ranging from 0.91 to 0.99. Again, the results for the CAGE were satisfactory (0.77), although inferior to the other instruments. Conclusions: The results obtained in this study confirm the validity of the abbreviated versions of the AUDIT for the screening of alcohol use disorders and show that their psychometric properties are as satisfactory as those of the 10-item AUDIT and the CAGE.

Subjective response to alcohol: a critical review of the literature.

Abstract: Background: Subjective response to alcohol (SR), which reflects individual differences in sensitivity to the pharmacological effects of alcohol, may be an important endophenotype in understanding genetic influences on drinking behavior and alcohol use disorders (AUDs). SR predicts alcohol use and problems and has been found to differ by a range of established risk factors for the development of AUDs (e.g., family history of alcoholism). The exact pattern of SR associated with increased risk for alcohol problems, however, remains unclear. The Low Level of Response Model (LLR) suggests that high-risk individuals experience decreased sensitivity to the full range of alcohol effects, while the Differentiator Model (DM) asserts that high risks status is associated with increased sensitivity to alcohol's positive effects but decreased sensitivity to negative effects. Aims: The current paper (1) reviews two prominent models of subjective response, (2) reviews extant laboratory-based research on subjective response, (3) highlights remaining gaps in our understanding and assessment of subjective response, and (4) encourages collaborative efforts to address these methodological and conceptual concerns. Methods: This paper reviews studies which employed placebo-controlled and non-placebo-controlled alcohol challenge paradigms to assess a range of alcohol effects including impairment, stimulation, and sedation. Results: The research literature provides at least partial support for both the LLR and DM models. High-risk individuals have been shown to have a reduced response to alcohol with respect to sedative or impairing effects, particularly on the descending limb of the blood alcohol curve (BAC). There is also evidence that ascending limb stimulant effects are more pronounced or operate differently for high-risk individuals. Discussion: Despite commendable advances in SR research, important questions remain unanswered. Inconsistent results across studies may be attributable to a combination of an inadequate understanding of the underlying construct and methodological differences across studies (e.g., number and timing of assessments across the BAC, inclusion of a placebo condition). With respect to the underlying construct, existing measures fail to adequately distinguish between cognitive/behavioral impairment and sedation, aspects of which may be perceived positively (e.g., anxiolysis) due to their ability to act as negative reinforcers. Conclusions: Addressing the concerns raised by the current review will be integral to making meaningful scientific progress in the field of subjective response. Language: en

Motivation for Alcohol Becomes Resistant to Quinine Adulteration After 3 to 4 Months of Intermittent Alcohol Self‐Administration

Abstract: Background Continued consumption of alcohol despite deleterious consequences is a hallmark of alcoholism and represents a critical challenge to therapeutic intervention. Previous rat studies showed that enduring alcohol self-administration despite pairing alcohol with normally aversive stimuli was only observed after very long-term intake (> 8 months). Aversion-resistant alcohol intake has been previously interpreted to indicate pathological or compulsive motivation to consume alcohol. However, given the time required to model compulsive alcohol seeking in previous studies, there is considerable interest in developing more efficient and quantitative rodent models of aversion-resistant alcohol self-administration.

MicroRNAs: master regulators of ethanol abuse and toxicity?

Abstract: Ethanol exerts complex effects on human physiology and health. Ethanol is not only addictive, but it is also a fetal teratogen, an adult neurotoxin, and an etiologic agent in hepatic and cardiovascular disease, inflammation, bone loss, and fracture susceptibility. A large number of genes and signaling mechanisms have been implicated in ethanol's deleterious effects leading to the suggestion that ethanol is a "dirty drug." An important question is, are there cellular "master-switches" that can explain these pleiotropic effects of ethanol? MicroRNAs (miRNAs) have been recently identified as master regulators of the cellular transcriptome and proteome. miRNAs play an increasingly appreciated and crucial role in shaping the differentiation and function of tissues and organs in both health and disease. This critical review discusses new evidence showing that ethanol-sensitive miRNAs are indeed regulatory master-switches. More specifically, miRNAs control the development of tolerance, a crucial component of ethanol addiction. Other drugs of abuse also target some ethanol-sensitive miRNAs suggesting that common biochemical mechanisms underlie addiction. This review also discusses evidence that miRNAs mediate several ethanol pathologies, including disruption of neural stem cell proliferation and differentiation in the exposed fetus, gut leakiness that contributes to endotoxemia and alcoholic liver disease, and possibly also hepatocellular carcinomas and other gastrointestinal cancers. Finally, this review provides a perspective on emerging investigations into potential roles of miRNAs as mediators of ethanol's effects on inflammation and fracture healing, as well as the potential for miRNAs as diagnostic biomarkers and as targets for therapeutic interventions for alcohol-related disorders.

Percentage of subjects with no heavy drinking days: evaluation as an efficacy endpoint for alcohol clinical trials.

Abstract: Background: Percent subjects with no heavy drinking days (PSNHDDs), an efficacy end point recommended by the Food and Drug Administration, considers abstinent individuals or those engaging in low-risk drinking behavior as successful responders to treatment. As PSNHDD has been used infrequently in previous alcohol clinical trials, we evaluated the utility and validity of the PSNHDD outcome measure in 2 large alcohol clinical trials. Methods: Data sets from 2 alcohol trials, COMBINE and a multisite topiramate trial, were used to analyze PSNHDDs and other traditional end points for the topiramate, naltrexone, acamprosate, and placebo groups. Effect sizes of PSNHDDs were determined for each month of active treatment and by varying grace periods-early periods in the trial where outcome is not considered in the analysis-and were compared with that of other traditional outcome measures. Long-term outcomes were compared for groups that had no heavy drinking days versus those that had heavy drinking days during active treatment. Results: PSNHDD effect sizes were significant for both topiramate (0.34 and 0.25 at months 2 and 3, respectively) and naltrexone (0.24 and 0.26 at months 3 and 4, respectively). Given a 2-month grace period for naltrexone, the effect size of PSNHDDs was comparable to the effect sizes using traditional outcome measures. With a 1-month grace period for topiramate, it was greater than the majority of traditional outcome measures. Little is gained by allowing up to 1, 2, or 3 heavy drinking days as an end point. Subjects with no HDDs during treatment fared better than those with some HDDs on drinking outcomes and alcohol-related consequences during a 1-year follow-up. Conclusions: PSNHDD appears to be a clinically informative end point measure, especially when used with a grace period, and is as sensitive as most traditional outcome measures in detecting differences between the medication and placebo groups. Nonetheless, these findings should be replicated in other clinical data sets, particularly with medications that work via different mechanisms. Language: en

Induction of innate immune gene expression cascades in brain slice cultures by ethanol: key role of NF-κB and proinflammatory cytokines.

Abstract: BACKGROUND Postmortem human alcoholic brain has increased expression of proinflammatory cytokines (He and Crews, 2007). Nuclear factor kappaB (NF-kappaB) is a transcription factor known to induce proinflammatory cytokine expression. Ethanol exposure increases NF-kappaB-DNA binding in rat brain (Crews et al., 2006) and in brain slice cultures in vitro (Zou and Crews, 2006). Using hippocampal-entorhinal cortex (HEC) brain slice cultures, we explored the effect of ethanol on NF-kappaB-DNA binding, proinflammatory gene expression, and sensitivity to glutamate neurotoxicity. METHODS The HEC brain slice cultures are prepared from rats on P7 and used after 2 weeks in culture. NF-kappaB-DNA binding is determined by EMSA, NF-kappaB subunit-DNA binding by ELISA and mRNA by RT-PCR. Multiple antibody immunohistochemistry and confocal microscopy are used to characterize cell types expressing ethanol-induced genes. RESULTS Ethanol treatment results in a progressive increase in NF-kappaB-DNA binding that includes large increases in NF-kappaB subunit p50 protein-DNA binding. The expression of NF-kappaB proinflammatory target genes progressively increased with time of ethanol treatment. Ethanol induces proinflammatory cytokines TNFalpha, MCP-1, and IL-1beta, proinflammatory proteases TACE, and tissue plasminogen activator (tPA) as well as inducible nitric oxide synthase. Blockade of NF-kappaB by using NF-kappaB p65 siRNA and BHT reduces ethanol induction of proinflammatory genes. Neutralizing antibody to proinflammatory cytokine TNFalpha reduces ethanol induction of proinflammatory genes, suggesting cytokine propagation of proinflammatory gene induction. Furthermore, neutralizing antibodies to proinflammatory cytokines and protease tPA inhibitors blunt ethanol sensitization to glutamate neurotoxicity. CONCLUSIONS These findings indicate that ethanol treatment increases NF-kappaB-DNA binding and proinflammatory gene expression in brain slices. Ethanol-induced innate immune proinflammatory gene induction alters neurotransmission and likely contributes to alcoholic neurodegeneration.

Alcohol biomarkers in applied settings: recent advances and future research opportunities.

Abstract: During the past decade, advances have been made in the identification, development, and application of alcohol biomarkers. This is important because of the unique functions that alcohol biomarkers can serve in various applied settings. To carry out these functions, biomarkers must display several features including validity, reliability, adequacy of temporal window of assessment, reasonable cost, and transportability. During the past two decades, several traditional alcohol biomarkers have been studied in multiple human studies. Meanwhile, several new, promising biomarkers, including various alcohol metabolites and alcohol biosensors, are being explored in human studies. In addition, researchers have explored using biomarkers in combination and using biomarkers in combination with self-reports, resulting in increased sensitivity with little sacrifice in specificity. Despite these advances, more research is needed to validate biomarkers, especially the new ones, in humans. Moreover, recent advances in high-throughput technologies for genomics, proteomics, and metabolomics offer unique opportunities to discover novel biomarkers, while additional research is needed to perfect newly developed alcohol sensors. Development of more accurate biomarkers will help practicing clinicians to more effectively screen and monitor individuals who suffer from alcohol use disorders.

Childhood sleep problems, response inhibition, and alcohol and drug outcomes in adolescence and young adulthood.

Abstract: Background: To our knowledge, no prospective studies examine the relationships among childhood sleep problems, adolescent executive functioning, and substance outcomes (i.e., substance use and substance-related problems). In this study, we examined whether childhood sleep problems predicted adolescent sleep problems and response inhibition. We also tested whether adolescent sleep problems and poor response inhibition mediated the relationship between childhood sleep problems and substance (alcohol and drug) outcomes in young adulthood. Methods: Study participants were 292 boys and 94 girls (M = 4.85, SD = 1.47) from a community sample of high-risk families and controls. Results: When compared to their counterparts, those with trouble sleeping in childhood were twice as likely to have the same problem in adolescence. Childhood overtiredness predicted poor response inhibition in adolescence. Persistent trouble sleeping from childhood to adolescence and response inhibition in adolescence mediated the relationship between childhood sleep problems and drug outcomes in young adulthood, whereas overtiredness in childhood directly predicted alcohol use outcomes and alcohol-related problems in young adulthood. Conclusions: This is the first study showing a long-term relationship between childhood sleep measures and subsequent alcohol and drug outcomes. The developmental and clinical implications of these findings were discussed. Prevention and intervention programs may want to consider the

Toward a Neurobehavioral Profile of Fetal Alcohol Spectrum Disorders

Abstract: Background A primary goal of recent research is the development of neurobehavioral profiles that specifically define fetal alcohol spectrum disorders (FASD), which may assist differential diagnosis or improve treatment. In the current study, we define a preliminary profile using neuropsychological data from a multisite study. Methods Data were collected using a broad neurobehavioral protocol from 2 sites of a multisite study of FASD. Subjects were children with heavy prenatal alcohol exposure and unexposed controls. The alcohol-exposed group included children with and without fetal alcohol syndrome (FAS). From 547 neuropsychological variables, 22 variables were selected for analysis based on their ability to distinguish children with heavy prenatal alcohol exposure from nonexposed controls. These data were analyzed using latent profile analysis (LPA). Results The results indicated that a 2-class model best fit the data. The resulting profile was successful at distinguishing subjects with FAS from nonexposed controls without FAS with 92% overall accuracy; 87.8% of FAS cases and 95.7% of controls were correctly classified. The same analysis was repeated with children with heavy prenatal alcohol exposure but without FAS and nonexposed controls with similar results. The overall accuracy was 84.7%; 68.4% of alcohol-exposed cases and 95% of controls were correctly classified. In both analyses, the profile based on neuropsychological variables was more successful at distinguishing the groups than was IQ alone. Conclusions We used data from 2 sites of a multisite study and a broad neuropsychological test battery to determine a profile that could be used to accurately identify children affected by prenatal alcohol exposure. Results indicated that measures of executive function and spatial processing are especially sensitive to prenatal alcohol exposure.

Delay discounting behavior and white matter microstructure abnormalities in youth with a family history of alcoholism.

Abstract: Background: Youth with family history of alcohol abuse have a greater risk of developing an alcohol use disorder (AUD). Brain and behavior differences may underlie this increased vulnerability. The current study examined delay discounting behavior and white matter microstructure in youth at high risk for alcohol abuse, as determined by a family history of alcoholism (FH+), and youth without such family history (FH−). Methods: Thirty-three healthy youth (FH+ = 15, FH− = 18), ages 11 to 15 years, completed a delay discounting task and underwent diffusion tensor imaging. Tract-based spatial statistics (Smith et al., 2006), as well as follow-up region-of-interest analyses, were performed to compare fractional anisotropy (FA) between FH+ and FH− youth. Results: FH+ youth showed a trend toward increased discounting behavior and had significantly slower reaction times (RTs) on the delay discounting paradigm compared to FH− youth. Group differences in FA were seen in several white matter tracts. Furthermore, lower FA in the left inferior longitudinal fasciculus and the right optic radiation statistically mediated the relationship between FH status and slower RTs on the delay discounting task. Conclusions: Youth with a family history of substance abuse have disrupted white matter microstructure, which likely contributes to less efficient cortical processing and may act as an intrinsic risk factor contributing to an increased susceptibility of developing AUD. In addition, FHP youth showed a trend toward greater impulsive decision making, possibly representing an inherent personal characteristic that may facilitate substance use onset and abuse in high-risk youth.

Magnetic Resonance Microscopy Defines Ethanol-Induced Brain Abnormalities in Prenatal Mice: Effects of Acute Insult on Gestational Day 7

Abstract: Background: This magnetic resonance microscopy (MRM)-based report is the second in a series designed to illustrate the spectrum of craniofacial and central nervous system (CNS) dysmorphia resulting from single- and multiple-day maternal ethanol treatment. The study described in this report examined the consequences of ethanol exposure on gestational day (GD) 7 in mice, a time in development when gastrulation and neural plate development begins; corresponding to the mid- to late third week postfertilization in humans. Acute GD 7 ethanol exposure in mice has previously been shown to result in CNS defects consistent with holoprosencephaly (HPE) and craniofacial anomalies typical of those in Fetal Alcohol Syndrome (FAS). MRM has facilitated further definition of the range of GD 7 ethanol-induced defects. Methods: C57Bl/6J female mice were intraperitoneally (i.p.) administered vehicle or 2 injections of 2.9 g/kg ethanol on day 7 of pregnancy. Stage-matched control and ethanol-exposed GD 17 fetuses selected for imaging were immersion fixed in a Bouins/Prohance solution. MRM was conducted at either 7.0 Tesla (T) or 9.4 T. Resulting 29 μm isotropic spatial resolution scans were segmented and reconstructed to provide 3D images. Linear and volumetric brain measures, as well as morphological features, were compared for control and ethanol-exposed fetuses. Following MRM, selected specimens were processed for routine histology and light microscopic examination. Results: Gestational day 7 ethanol exposure resulted in a spectrum of median facial and forebrain deficiencies, as expected. This range of abnormalities falls within the HPE spectrum; a spectrum for which facial dysmorphology is consistent with and typically is predictive of that of the forebrain. In addition, other defects including median facial cleft, cleft palate, micrognathia, pituitary agenesis, and third ventricular dilatation were identified. MRM analyses also revealed cerebral cortical dysplasia/heterotopias resulting from this acute, early insult and facilitated a subsequent focused histological investigation of these defects. Conclusions: Individual MRM scans and 3D reconstructions of fetal mouse brains have facilitated demonstration of a broad range of GD 7 ethanol-induced morphological abnormality. These results, including the discovery of cerebral cortical heterotopias, elucidate the teratogenic potential of ethanol insult during the third week of human prenatal development.

Prenatal Alcohol Exposure and Chronic Mild Stress Differentially Alter Depressive- and Anxiety-Like Behaviors in Male and Female Offspring

Abstract: Background: Fetal Alcohol Spectrum Disorder (FASD) is associated with numerous neurobehavioral alterations, as well as disabilities in a number of domains, including a high incidence of depression and anxiety disorders. Prenatal alcohol exposure (PAE) also alters hypothalamicpituitary-adrenal (HPA) function, resulting in increased responsiveness to stressors and HPA dysregulation in adulthood. Interestingly, data suggest that pre-existing HPA abnormalities may be a major contributory factor to some forms of depression, particularly when an individual is exposed to stressors later in life. We tested the hypothesis that exposure to stressors in adulthood may unmask an increased vulnerability to depressive- and anxiety-like behaviors in PAE animals. Methods: Male and female offspring from prenatal alcohol (PAE), pair-fed (PF), and ad libitumfed control (C) treatment groups were tested in adulthood. Animals were exposed to 10 consecutive days of chronic mild stress (CMS), and assessed in a battery of well-validated tasks sensitive to differences in depressive- and ⁄ or anxiety-like behaviors. Results: We report here that the combination of PAE and CMS in adulthood increases depressive- and anxiety-like behaviors in a sexually dimorphic manner. PAE males showed impaired hedonic responsivity (sucrose contrast test), locomotor hyperactivity (open field), and alterations in affiliative and nonaffiliative social behaviors (social interaction test) compared to control males. By contrast, PAE and, to a lesser extent, PF, females showed greater levels of ‘‘behavioral despair’’ in the forced swim test, and PAE females showed altered behavior in the final 5 minutes of the social interaction test compared to control females. Conclusions: These data support the possibility that stress may be a mediating or contributing factor in the psychopathologies reported in FASD populations.

Ethanol-regulated genes that contribute to ethanol sensitivity and rapid tolerance in Drosophila.

Abstract: Background—Increased ethanol intake, a major predictor for the development of alcohol use disorders, is facilitated by the development of tolerance to both the aversive and pleasurable effects of the drug. The molecular mechanisms underlying ethanol tolerance development are complex and are not yet well understood. Methods—To identify genetic mechanisms that contribute to ethanol tolerance, we examined the time course of gene expression changes elicited by a single sedating dose of ethanol in Drosophila, and completed a behavioral survey of strains harboring mutations in ethanol-regulated genes. Results—Enrichment for genes in metabolism, nucleic acid binding, olfaction, regulation of signal transduction, and stress suggests that these biological processes are coordinately affected by ethanol exposure. We also detected a coordinate up-regulation of genes in the Toll and Imd innate immunity signal transduction pathways. A multi-study comparison revealed a small set of genes showing similar regulation, including increased expression of 3 genes for serine biosynthesis. A survey of Drosophila strains harboring mutations in ethanol-regulated genes for ethanol sensitivity and tolerance phenotypes revealed roles for serine biosynthesis, olfaction, transcriptional regulation, immunity, and metabolism. Flies harboring deletions of the genes encoding the olfactory co-receptor Or83b or the sirtuin Sir2 showed marked changes in the development of ethanol tolerance. Conclusions—Our findings implicate novel roles for these genes in regulating ethanol behavioral responses.

Consequences of an Adolescent Onset and Persistent Course of Alcohol Dependence in Men: Adolescent Risk Factors and Adult Outcomes

Abstract: Background: While there is an extensive literature on the correlates of alcohol use disorders (AUD; alcohol abuse and dependence), there are relatively few prospective studies of representative birth cohorts that have examined the unique effects of an adolescent onset and persistent course of AUD on a wide range of psychosocial variables. Methods: A longitudinal, community-based sample of 530 men was used to examine the impact of an adolescent onset (AUD+ at age 17) and persistent course (AUD+ at age 29) of AUD on adolescent and adult functioning including substance use, antisocial behavior, mental health problems, overall psychosocial functioning, environmental risk and protective factors, and social outcomes such as peer and romantic relationships, marriage, educational and occupational attainment, and parenthood. Results: An adolescent onset of AUD (n = 57) was associated with severe deficits across multiple domains of psychosocial functioning in adolescence. Measures of behavioral disinhibition in adolescence were strong predictors of a persistent course of AUD (n = 93). Nearly 40% of men with an adolescent onset were able to desist by age 29, and were similar, but not identical to men who never experienced an AUD in terms of adult functioning. Men with an adolescent onset and persistent course of AUD exhibited the most severe deficits in functioning. Conclusion: Results emphasize the importance of examining developmental course to understand the etiology of AUD. Our findings are optimistic in that individuals who desist from AUD are able to achieve high levels of psychosocial functioning. Our findings suggest that future research on the persistence of AUD into adulthood should focus on the contributions of behavioral disinhibition and social environment variables including peer and romantic relationships.

Ghrelin receptor antagonism decreases alcohol consumption and activation of perioculomotor urocortin-containing neurons

Abstract: Recent reports showing an overlap in the neural pathways responsible for obesity and those involved in excessive alcohol use (for review see Thiele et al., 2003) suggest that orexigenic peptides are promising targets for pharmacotherapy of alcoholism. The orexigenic peptide ghrelin, produced in the gastric fundic mucosa (Korbonits et al., 2004; Nakazato et al., 2001), causes the secretion of growth hormone, and acts to stimulate appetite and food intake (Locke et al., 1995; Wren et al., 2000). Ghrelin is also expressed in the hypothalamus, namely in the lateral hypothalamus, the arcuate nucleus (Arc), the ventromedial nucleus, dorsomedial nucleus and the paraventricular nucleus (Cowley et al., 2003; Hou et al., 2006; Kageyama et al., 2008; Kojima et al., 1999). The receptor at which ghrelin acts to stimulate the release of growth hormone is the growth hormone secretagogue receptor 1a (GHSR 1a) (Kojima et al., 1999; van der Lely et al., 2004). Zigman et al. (2006) showed that in the mouse, high levels of GHSR 1a mRNA occur in the perioculomotor urocortin-containing neurons (pIIIu, formerly known as the Edinger-Westphal nucleus; Horn et al., 2008; May et al., 2008). GHSR 1a mRNA is also abundant in the Arc (Tannenbaum et al., 1998; Willesen et al., 1999; Zigman et al. 2006) where the main targets of ghrelin are the neuropeptide Y/Agouti-related protein neurons and the leptin-responsive neurons (Traebert et al., 2002). Other regions of the brain where GHS 1a receptor mRNA is expressed, albeit in substantially lesser amounts than the Arc and pIIIu, include the ventral tegmental area (VTA), the laterodorsal tegmental area and the hippocampus (Guan et al., 1997; Zigman et al., 2006). Ghrelin has been studied extensively with regards to food intake and obesity (for review see Neary et al., 2003). Ghrelin is secreted in anticipation of a meal, and ghrelin levels decrease after food has been consumed (Cummings et al., 2001; Drazen et al., 2006). Central or systemic ghrelin increases food intake, and the effects of ghrelin on feeding and weight gain involve the Arc (Nakazato et al., 2001; Ruter et al., 2003; Wren et al., 2000). The peripheral administration of a GHSR antagonist, D-Lys3-GHRP-6, in contrast, reduced food intake as well as weight gain (Asakawa et al., 2003). Recent studies have also started to implicate ghrelin in alcohol drinking. Increased plasma levels of ghrelin have been reported in active drinkers, alcohol-dependent female patients, in alcohol withdrawal groups and in alcohol abstainers (Kim et al., 2005; Kraus et al., 2005; Wurst et al., 2007). A single nucleotide polymorphism in the GHSR 1a gene was found to be associated with heavy alcohol drinking in a Spanish population (Landgren et al., 2008). In mice, centrally administered ghrelin increased alcohol drinking while the GHSR 1a antagonists, BIM28163 and JMV2959, reduced alcohol consumption. The increased alcohol intake in response to centrally administered ghrelin was also found to be absent in GHSR 1a knock-out mice (Jerlhag et al., 2009b), showing that ghrelin acts at the GHSR 1a to affect alcohol-seeking behavior. However, conflicting findings showing reduced plasma and stomach ghrelin levels in alcohol-dependent patients have also been reported (Badaoui et al., 2008). In normal volunteers, plasma ghrelin levels were reduced after acute alcohol (Calissendorff et al., 2005; Zimmermann et al., 2007). Addolorato et al. (2006) showed decreased ghrelin levels in alcohol-dependent patients compared to healthy subjects, but the authors also found a positive correlation between ghrelin levels and craving for alcohol. Lyons et al. (2008) reported that systemic ghrelin does not affect alcohol consumption in a “drinking in the dark” (DID) procedure in food-deprived C57BL/6J mice. Thus, the relationship between ghrelin and alcohol consumption and alcoholism still needs to be clarified. It may be important to understand the neural substrates of ghrelin to clarify this relationship. Jerlhag et al. (2009b) showed that administering ghrelin, either intracerebroventricularly or into the VTA increased alcohol intake in mice whereas administering GHSR 1a antagonists, centrally or systemically, reduced alcohol intake. Thus, the authors concluded that ghrelin acting in the tegmental regions was responsible for the rewarding effects of alcohol. However, the VTA is located physically close to the pIIIu, and as observed in the Allen Brain Atlas (http://www.brain-map.org) and reported by Zigman et al. (2006), it contains substantially lower levels of GHSR1a mRNA than pIIIu. Several studies, using c-Fos expression mapping, electrolytic lesion of the pIIIu and rodents selectively bred for differences in alcohol intakes, have shown that the pIIIu is involved in the regulation of alcohol-related phenotypes, including high alcohol intake (Bachtell et al., 1999; Bachtell et al., 2002a; Bachtell et al., 2002b; Bachtell et al., 2003; Bachtell et al., 2004; Fonareva et al., 2009; Ryabinin et al., 2001; Ryabinin et al., 2003; Sharpe et al., 2005; Topple et al., 1998; Turek et al., 2005; Weitemier et al., 2001; Weitemier and Ryabinin, 2005). The Arc contains GHSR 1a receptors at levels comparable to the pIIIu (Zigman et al., 2006). Lesion and microinjection studies have implicated the Arc in ethanol-induced locomotor activation (Pastor and Aragon, 2008; Sanchis-Segura et al., 2000). It is, therefore, important to understand whether ghrelin acts via the VTA, pIIIu or Arc to regulate alcohol-related behaviors. In the current study, we investigated the neuroanatomical locus/loci through which ghrelin acts to regulate alcohol consumption. At first we confirmed that the ghrelin receptor antagonist that we used, D-Lys3-GHRP-6 acts to decrease alcohol preference in C57BL/6J mice in a similar fashion to the GHSR antagonists used by Jerlhag and colleagues (2009b). Following this confirmation, we investigated the effects of D-Lys3-GHRP-6 on c-Fos immunoreactivity induced in pIIIu, VTA and Arc by alcohol intake in the drinking in the dark procedure and by systemic administration of ethanol. We also determined if D-Lys3-GHRP-6 affects blood ethanol concentrations after systemic ethanol administration.

Alcohol expectancies and drinking refusal self-efficacy mediate the association of impulsivity with alcohol misuse.

Abstract: Background: Recent work suggests that 2 biologically based traits convey risk for alcohol misuse: reward sensitivity/drive and (rash) impulsiveness. However, the cognitive mechanisms through which these traits convey risk are unclear. This study tested a model predicting that the risk conveyed by reward sensitivity is mediated by a learning bias for the reinforcing outcomes of alcohol consumption (i.e., positive alcohol expectancy). The model also proposed that the risk conveyed by rash impulsiveness (RI) is mediated by drinkers' perceived ability to resist alcohol (i.e., drinking refusal self-efficacy). Methods: Study 1 tested the model in a sample of young adults (n = 342). Study 2 tested the model in a sample of treatment-seeking substance abusers (n = 121). All participants completed a battery of personality, cognitive, and alcohol use questionnaires and models were tested using structural equation modeling. Results: In both studies, the hypothesized model was found to provide a good fit to the data, and a better fit than alternative models. In both young adults and treatment-seeking individuals, positive alcohol expectancy fully mediated the association between reward sensitivity and hazardous alcohol use. For treatment seekers, drinking refusal self-efficacy fully mediated the association between RI and hazardous drinking. However, there was partial mediation in the young adult sample. Furthermore, neither trait was directly associated with the other cognitive mediator. Conclusions: The hypothesized model was confirmed on a large sample of young adults and replicated on a sample of treatment-seeking substance abusers. Taken together, these findings shed further light on the mechanisms through which an impulsive temperament may convey risk for alcohol misuse. Language: en

Disability associated with alcohol abuse and dependence.

Abstract: Background: Alcohol use disorders (AUD), i.e., alcohol dependence and abuse, are major contributors to burden of disease. A large part of this burden is because of disability. However, there is still controversy about the best disability weighting for AUD. The objective of this study was to provide an overview of alcohol-related disabilities. Methods: Systematic literature review and expert interviews. Results: There is heterogeneity in experts’ descriptions of disabilities related to AUD. The major core attributes of disability related to AUD are changes of emotional state, social relationships, memory and thinking. The most important supplementary attributes are anxiety, impairments of speech and hearing. Conclusions: This review identified the main patterns of disability associated with AUD. However, there was considerable variability, and data on less prominent patterns were fragmented. Further and systematic research is required for increasing the knowledge on disability related to AUD and for application of interventions for reducing the associated burden.

Brain microstructure is related to math ability in children with fetal alcohol spectrum disorder.

Abstract: Background: Children with fetal alcohol spectrum disorder (FASD) often demonstrate a variety of cognitive deficits, but mathematical ability seems to be particularly affected by prenatal alcohol exposure. Parietal brain regions have been implicated in both functional and structural studies of mathematical ability in healthy individuals, but little is known about the brain structure underlying mathematical deficits in children with FASD. The goal of this study was to use diffusion tensor imaging (DTI) to investigate the relationship between mathematical skill and brain white matter structure in children with FASD. Methods: Twenty-one children aged 5 to 13 years diagnosed with FASD underwent DTI on a 1.5-T MRI scanner and cognitive assessments including the Woodcock-Johnson Quantitative Concepts test. Voxel-based analysis was conducted by normalizing subject images to a template and correlating fractional anisotropy (FA) values across the brain white matter with age-standardized math scores. Results: Voxel-based analysis revealed 4 clusters with significant correlations between FA and math scores: 2 positively-correlated clusters in the left parietal region, 1 positively-correlated cluster in the left cerebellum, and 1 negatively-correlated cluster in the bilateral brainstem. Diffusion tractography identified the specific white matter tracts passing through these clusters, namely the left superior longitudinal fasciculus, left corticospinal tract and body of the corpus callosum, middle cerebellar peduncle, and bilateral projection fibers including the anterior and posterior limbs of the internal capsule. Conclusions: These results identify 4 key regions related to mathematical ability and provide a link between brain microstructure and cognitive skills in children with FASD. Given previous findings in typically developing children and those with other abnormal conditions, our results highlight the consistent importance of the left parietal area for mathematical tasks across various populations, and also demonstrate other regions that may be specific to mathematical processing in children with FASD.

Implementation of NIAAA College Drinking Task Force recommendations: how are colleges doing 6 years later?

Abstract: Background: In 2002, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) College Drinking Task Force issued recommendations to reduce heavy drinking by college students, but little is known about implementation of these recommendations. Current discussion about best strategies to reduce student drinking has focused more on lowering the minimum legal drinking age as advocated by a group of college and university presidents called the Amethyst Initiative than the NIAAA recommendations. Methods: A nationally representative survey of administrators was conducted at 351 4-year colleges in the United States to ascertain familiarity with and progress toward implementation of NIAAA recommendations. Implementation was compared by enrollment size, public or private status, and whether the school president signed the Amethyst Initiative. Results: Administrators at most colleges were familiar with NIAAA recommendations, although more than 1 in 5 (22%) were not. Nearly all colleges use educational programs to address student drinking (98%). Half the colleges (50%) offered intervention programs with documented efficacy for students at high risk for alcohol problems. Few colleges reported that empirically supported, community-based alcohol control strategies including conducting compliance checks to monitor illegal alcohol sales (33%), instituting mandatory responsible beverage service (RBS) training (15%), restricting alcohol outlet density (7%), or increasing the price of alcohol (2%) were operating in their community. Less than half the colleges with RBS training and compliance checks in their communities actively participated in these interventions. Large colleges were more likely to have RBS training and compliance checks, but no differences in implementation were found across public ⁄ private status or whether the college president signed the Amethyst Initiative. Conclusions: Many colleges offer empirically supported programs for high-risk drinkers, but few have implemented other strategies recommended by NIAAA to address student drinking. Opportunities exist to reduce student drinking through implementation of existing, empirically based strategies.

Interactive Effects of Cumulative Stress and Impulsivity on Alcohol Consumption

Abstract: The influence of environmental factors such as stress and individual difference traits such as impulsivity on the development and course of alcohol dependence are well established in both human and animal literature (Evenden, 1999a; Sinha, 2008). Neuroadaptations to stress systems have been shown to underlie the pathophysiology of alcohol, as well as stimulant, opioid, and nicotine addiction (Fox and Sinha, 2009 for review). Well-established human models of addiction such as stress-coping (Wills and Shiffman, 1985) and relapse prevention models (Marlatt and Gordon, 1985) have also presented problem drinking as a maladaptive coping response to life stressors. In addition, both animal and human studies have shown that impulsivity, in terms of impulsive choice and inhibitory failure, is also paramount to the acquisition and escalation of alcohol and substance abuse (Perry and Carroll, 2008 for review). Although both stress and impulsivity are independent risk factors for drinking, few studies have investigated the nature of their interactive relationship in terms of harmful and hazardous drinking patterns. The interactive nature of stress regulatory mechanisms on drinking is highlighted by genetic research investigating the impact on drinking of various levels of life adversity and genetic markers implicated in regulatory behavior. For example, young adults exposed to high levels of psychosocial adversity and carrying the long variant of the serotonin transporter gene exhibit greater hazardous drinking compared with those carrying the short allele or not exposed to high levels of adversity (Laucht et al., 2009). This serotonin transporter gene polymorphism has also been shown to interact with rearing stress in nonhuman primates (Barr et al., 2004) as well as stressful life events in adolescents and young adults (Covault et al., 2007; Kaufman et al., 2007; Olsson et al., 2005) with regard to increased drinking patterns and greater nonprescription dug use. While these studies have assessed genetic markers linked to behaviors associated with impulsivity (Paaver et al., 2007; Wagner et al., 2009), a more direct relationship between various aspects of subjective trait impulsivity and cumulative life stress on problem drinking behaviors have not been evaluated within a local community sample of volunteers. Therefore, current study examines the relationship between various types of stress and different aspects of impulsivity on alcohol use and alcohol-related problems as assessed by the Alcohol Use Disorders Identification Test (AUDIT; Babor et al., 2001). Both epidemiological and clinical research has indicated that recent life stress (Perkins, 1999; Rutledge and Sher, 2001), cumulative adverse life events, including life traumas (Lloyd and Turner, 2008; Turner and Lloyd, 2003), and traumatic life experiences (Breslau et al., 2003; Reed et al., 2007) have all been positively associated with increases in drinking and substance abuse. However, diverse types of stress may differentially affect biopsychological markers associated with drinking vulnerability, showing certain stressors to be stronger indicators of problem drinking than others. For example, while traumatic or enduring stress has been associated with reduced cortisol response to stress exposure (Geracioti et al., 2008), daily stress has been associated with increased cortisol activity (Brantley et al., 1988; Roy et al., 2003;). Similarly, heart rate variability (HRV) and dopamine (DA) neurotransmission have also been shown to differ with regard to whether stressors are acute or chronic (Farah et al., 2004; Kalivas and Duffy, 1995; Lucas et al., 2004). In the current study, we use a comprehensive cumulative stress measure adapted from Turner and Wheaton (1995) to assess recent adverse life events as well as cumulative traumatic stress, major life events, and chronic stress. Similarly, impulsivity is a multidimensional construct (Evenden, 1999b; de Wit, 2009) defined in the literature by a wide range of paradigms (Evenden, 1999a for review). In general, however, behavioral studies have indicated that impulsive choice (or failure to delay gratification) and response inhibition are most relevant to the transition from controlled to compulsive drinking (Evenden, 1999a; Perry and Carroll, 2008; Rubio et al., 2007). In the current study, we use the BIS-11 (Patton et al., 1995) a widely used and well standardized measure of impulse control likely to provide a reliable subjective index of these regulatory processes. While the Nonplanning subscale of the BIS has been associated with performance on delayed discounting tests as both may reflect an insensitivity to future gratification (de Wit et al., 2007), the Attention and Motor subscales have been shown to correlate with inhibitory control-related tasks including Go No Go and Trails B (Asahi et al., 2004; Keilp et al., 2005; Spinella, 2007). We therefore aim to assess the effects of life adversity and trait impulsivity on alcohol use and alcohol-related problems, as measured by the AUDIT in a community sample. Establishing the nature and relative contribution of both stress and impulsivity to at-risk drinking within a community sample will help determine better tailored intervention programs focused on prevention and the progression of alcohol abuse.

Sensory processing and adaptive behavior deficits of children across the fetal alcohol spectrum disorder continuum

Abstract: Background: Prenatal alcohol exposure can have detrimental effects on a child’s development of adaptive behaviors necessary for success in the areas of academic achievement, socialization, and self-care. Sensory processing abilities have been found to affect a child’s ability to successfully perform adaptive behaviors. The current study explored whether significant differences in sensory processing abilities, adaptive behavior, and neurocognitive functioning are observed between children diagnosed with partial Fetal Alcohol Syndrome (pFAS), Alcohol-Related Neurodevelopmental Disorder (ARND), or children who were prenatally exposed to alcohol (PEA), but did not meet criteria for an FASD diagnosis. The influence of IQ on adaptive behavior as well as further exploration of the relationship between sensory processing and adaptive behavior deficits among these children was also examined. Methods: A secondary analysis was conducted on some of the Short Sensory Profile (SSP) scores, Adaptive Behavior Assessment System—Second Edition (ABAS-II) scores, and Wechsler Intelligence Scale—Fourth Edition/Wechsler Preschool and Primary Scale of Intelligence—Third Edition (WISC- IV/WPPSI—III) scores of 46 children between 3 and 14 years of age with pFAS, ARND, or who were PEA. Results: Greater sensory processing deficits were found in children with a diagnosis of pFAS and ARND compared to those in the PEA group. Children with an ARND diagnosis scored significantly worse on measures of adaptive behavior than the PEA group. Children with pFAS scored significantly lower than children with ARND or PEA on perceptual/performance IQ. No correlation was found between IQ scores and adaptive behaviors across the FASD diagnostic categories. A significant positive correlation was found between SSP and ABAS-II scores. Conclusions: Regardless of the diagnosis received under the FASD umbrella, functional difficulties that could not be observed using traditional measures of intelligence were found, supporting guidelines that a broad range of standardized assessments be included when screening children for FASD.

Human variation in alcohol response is influenced by variation in neuronal signaling genes.

Abstract: Background: Alcohol use disorders (AUD) exhibit the properties shared by common conditions and diseases classified as genetically complex. The etiology of AUDs is heterogeneous involving mostly unknown interactions of environmental and heritable factors. A person’s level of response (LR) to alcohol is inversely correlated with a family history and the development of AUDs. As an AUD endophenotype, alcohol LR is hypothesized to be less genetically complex and closer to the primary etiology of AUDs. Methods: A genome wide association study (GWAS) was performed on subjects characterized for alcohol LR phenotypes. Gene Set Enrichment Analysis (GSEA) of the GWAS data was performed to determine whether, as a group, genes that participate in a common biological function (a gene set) demonstrate greater genetic association than would be randomly expected. Results: The GSEA analysis implicated variation in neuronal signaling genes, especially glutamate signaling, as being involved in alcohol LR variability in the human population. Conclusions: These data, coupled with cell and animal model data implicating neuronal signaling in alcohol response, support the conclusion that neuronal signaling is mechanistically involved in alcohol’s cellular and behavioral effects. Further, these data suggest that genetic variation in these signaling pathways contribute to human variation in alcohol response. Finally, this concordance of the cell, animal, and human findings supports neuronal signaling, particularly glutamate signaling, as a prime target for translational studies to understand and eventually modulate alcohol’s effects.

Ethanol-induced conditioned taste aversion in male sprague-dawley rats: impact of age and stress.

Abstract: Adolescence is a developmental period characterized by considerable transformations that are highly conserved across species. In addition to neural and hormonal changes, increases in social activity, novelty seeking, impulsivity and risk-taking are frequently reported during this transitional phase (see Spear, 2000; 2010). In line with these behavioral changes, alcohol use is commonly initiated during adolescence. Survey results from the 2008 Monitoring the Future study indicate that as many as 72% of high school seniors have tried alcohol at least once and that nearly 30% have been drunk in the past 30 days (Johnston et al., 2009). Elevated ethanol intake is characteristic of rodent models of adolescence as well, using a conservative age range (postnatal days [P] 28 to 42) to typify the developmental period during which adolescent-characteristic neural and behavioral features are evident in both males and females (Spear, 2000). Adolescent rats often voluntarily consume 2–3 times more ethanol than do adults (Brunell and Spear, 2005; Doremus et al., 2005; Vetter et al., 2007). For this reason, animal models of adolescence are particularly useful in examining factors that may contribute to the age-related elevation of ethanol consumption, given ethical constraints limiting this line of research in human subjects. There are several age-specific characteristics that may lead to elevated ethanol consumption during adolescence. For example, adolescents appear to be more sensitive to the social-facilitating effects of ethanol (Varlinskaya and Spear, 2002) and less sensitive than adults to many of the aversive consequences of ethanol that may serve as cues to curb intake, such as motor impairment (Hollstedt et al., 1980; Silveri and Spear, 2001; White et al., 2002), suppression of locomotor activity (Little et al., 1996), social impairment (Varlinskaya and Spear, 2002), and sedation (Draski et al., 2001; Moy et al., 1998; Silveri and Spear, 1998; 1999; 2002; 2004). Additionally, adolescent rats experience attenuated anxiogenesis compared to adults following acute ethanol withdrawal (Doremus et al., 2003; Varlinskaya and Spear, 2004). Together these age-related differences in sensitivity to various effects of ethanol may permit or even encourage higher ethanol consumption by adolescents relative to adults. Conditioned taste aversion (CTA) is one method used to assess the dysphoric effects of alcohol and other drugs. This procedure involves the ingestion of a novel-flavored solution (conditioned stimulus; CS) paired with the effects of a particular drug (unconditioned stimulus; US). When given a subsequent opportunity to consume the drug-paired flavor, the degree to which an animal avoids the solution provides an index of the relative dysphoria experienced following the previous encounter with the drug. Supporting this interpretation, Green and Grahame (2008) report that CTA negatively correlates with ethanol intake across a wide variety of strains and selected lines of rats and mice, suggesting that low sensitivity to the aversive properties of ethanol may facilitate high ethanol intake. A recent study in our laboratory (Vetter-O'Hagen et al., 2009) demonstrated an age-related insensitivity to ethanol-induced taste aversion using saccharin as a CS, with both male and female adolescents requiring higher doses of ethanol than their adult counterparts to elicit a CTA. This initial study exploring the role of social context in sensitivity to the dysphonic effects of ethanol reported that adolescent males (but not females) who were exposed to an unfamiliar social partner for 24 hr following the pairing of ethanol with a saccharin solution CS demonstrated an attenuated sensitivity to the aversive properties of ethanol relative to males that remained isolated for this period. While the previously reported reduction in sensitivity to ethanol’s effect in the presence of a partner among adolescent males was interpreted as an effect of social experience during intoxication (Vetter-O’Hagen et al., 2009), we cannot preclude that exposure to an unfamiliar conspecific may have been stressful for a test subject. Therefore, the decreases in sensitivity to the aversive properties of ethanol seen in that CTA paradigm might have been stress-induced. Human adolescents are confronted with a number of social and environmental challenges that are potentially stressful (Buchanan et al., 1992; Spear, 2000), and drinking to cope with problems is associated with extensive alcohol use in adolescence (Cooper et al., 2000). Research conducted in laboratory animals, although still limited, has revealed age-related differences in responsiveness to stressors, with adolescent rodents sometimes displaying increased sensitivity to stressors when indexed via hormonal responses as well as behavioral alterations (Brunell and Spear, 2005; Doremus-Fitzwater et al., 2009; Romeo et al., 2006; Stone and Quartermain, 1997). Given these ontogenetic differences in stress responses, it is possible that exposure to stressors might differentially impact sensitivity to the aversive effects of ethanol in adolescents compared to adults. Some experimental evidence suggests that exposure to stressors either immediately before or after ingestion of the CS may attenuate CTA (Misanin et al., 2006; Bourne et al., 1991; Revusky & Reilly, 1989), likely via an interruption in the learned association between the CS and US. However, no attempts have been made to assess age-related differences in stress-induced alterations using ethanol-induced CTA. Therefore, the effects of two different stressors on ethanol-induced CTA were examined in adolescent and adult animals in the present experiments: Repeated restraint (Experiment 1) and isolate-housing (Experiment 2). An additional explanation for the elevated ethanol consumption commonly reported during adolescence involves possible age-related differences in hedonic sensitivity. In general, consummatory behaviors toward appetitive stimuli (such as food and other natural rewards) increase during adolescence. This change may be due to alterations in the hedonic value of the stimuli; that is, individuals at this age may consume more of a particular reinforcer either because they find it more rewarding or because they find it less rewarding and must consume more in order to achieve the positive consequences. If adolescents do indeed exhibit a partial anhedonia, they may seek out more natural and drug rewards to compensate for this age-related insensitivity to natural reinforcers. Sucrose consumption and preference are measures commonly used as a presumptive index of anhedonia (Katz, 1982; Konkle et al., 2003; Matthews et al., 1995; Willner et al., 1987), given evidence that animals subjected to chronic mild stress (an animal model of depression) typically reduce their intake of sweetened solutions (Gronli et al., 2004; Willner et al., 1987). There is some evidence that sucrose intake is generally more affected by prior stress exposure than that of saccharin (Harris et al., 1998; Gronli et al., 2005). In order to allow for assessment of hedonic sensitivity at both ages, sucrose, but not saccharin (Vetter-O’Hagen et al., 2009) was chosen as the CS in the present study, with the baseline sucrose consumption (prior to ethanol exposure) serving as an index of relative of stress-induced anhedonia. Given that our previous study revealed no sex differences in ethanol-induced CTA in adult animals and decreased sensitivity to the aversive properties of ethanol when intoxication occurred in the presence of the peer in adolescent male but not female rats (Vetter-O’Hagen et al., 2009), only male subjects were used in the present experiments.