Background: Abstinent alcoholics have deficits in comprehending the affective intonation in speech. Prior work suggests that these deficits are due to alcohol exposure rather than preexisting risk factors for alcoholism. The present paper examines whether family history of alcoholism is a contributor to affective prosody deficits in alcoholics. Methods: Fifty-eight healthy, nonabusing young adults with and without a family history of alcoholism or other substance abuse (29 FH+ and 29 FH−) were compared on affective prosody comprehension using the Aprosodia Battery. A secondary analysis was done comparing affective prosody comprehension in FH+ and FH− detoxified alcoholics from an earlier study (17 FH+ and 14 FH−). Results: Performance on the Aprosodia Battery was not related to FH status in either the healthy, nonabusing sample or in the detoxified alcoholic group. Conclusions: The present study lends support to previous research suggesting that deficits in affective prosody comprehension observed in detoxified alcoholics are associated with a history of heavy drinking rather than with a family history of alcoholism.
Aims: Alcohol expectancies are strong concurrent predictors of alcohol use and problems, but the current study addressed their unique power to predict from adolescence to midlife. Method: Long-term longitudinal data from the national British Cohort Study 1970 (N = 2146, 59.8% female) were used to predict alcohol use and misuse in the mid-30s by alcohol expectancies reported in adolescence. Results: Cohort members with more positive alcohol expectancies at age 16 reported greater alcohol quantity concurrently, increases in alcohol quantity relative to their peers between ages 16 and 35, and a higher likelihood of lifetime and previous year alcohol misuse at age 35, independent of gender, social class in family of origin, age of alcohol use onset, adolescent delinquent behavior and age 16 exam scores. Conclusions: Alcohol expectancies were strong proximal predictors of alcohol use and predicted relative change in alcohol use and misuse across two decades into middle adulthood.
Aim: The aim of this study was to assess whether chronic alcohol misuse affects N-methyl-d-aspartate (NMDA) receptor subunit concentrations in human cases, and whether male and female subjects respond differently. Methods: Real-time RT-PCR normalized to GAPDH was used to assay NR1, NR2A and NR2B subunit mRNA in superior frontal (SFC) and primary motor (PMC) cortex tissue obtained at autopsy from chronic alcoholics with and without comorbid cirrhosis of the liver, and from matched controls. Results: The expression of all three subunits was significantly lower in both areas of cirrhotic alcoholics than in either controls or alcoholics without comorbid disease, who did not differ significantly. Values were also influenced by the subject's sex and genotype. The μ-opiate receptor C1031G polymorphism selectively modulated NMDA transcript expression in cirrhotic-alcoholic SFC, an effect that was more marked for NR1 and NR2A than for NR2B subunit transcripts. Contrasting 5HT1B genotypes affected NMDA mRNA expression differently in male and female SFC, but not PMC, in cirrhotic alcoholics. Conclusion: NMDA receptor subunit expression may differentially influence male and female cirrhotic alcoholics’ susceptibility to brain damage.
Aims: Chronic alcohol and drug dependence leads to neuroadaptations in hypothalamic–pituitary–adrenal (HPA) and sympathetic adrenal medullary (SAM) stress systems, which impact response sensitivity to stress and alcohol cue and facilitates risk of relapse. To date, gender variations in these systems have not been fully assessed in abstinent alcohol-dependent individuals who also met criteria for cocaine abuse. Methods: Forty-two (21 M/21 F) early abstinent treatment-seeking substance-abusing (SA) men and women and 42 (21 M/21 F) healthy control (HC) volunteers were exposed to three 5-min guided imagery conditions (stress, alcohol/drug cue, neutral relaxing), presented randomly, one per day across three consecutive days. Alcohol craving and anxiety ratings were obtained as well as measures of heart rate (HR), blood pressure, plasma ACTH, cortisol, norepinephrine (NE) and epinephrine (EPI). Results: SA males showed increased ACTH and EPI basal tone compared with HC males and SA females. However, they demonstrated no increase in ACTH and cortisol levels following stress and alcohol cue imagery exposure compared to the neutral condition. SA females demonstrated a typically increased stress response in both measures. In addition, SA males showed no increase in cardiovascular response to either stress or cue, and no increase in catecholamine response to cue compared with their response to neutral imagery. Again, this dampening was not observed in HC males who produced significantly higher levels of cue-related HR and EPI, and significantly higher stress-related DBP. In contrast, SA females showed an enhanced ACTH and cortisol response to stress and cue compared with neutral imagery and this was not observed in the HC females. They also demonstrated a reduced increase in NE and EPI compared with both SA males and HC females as well as reduced HR compared with HC females. Conclusions: While SA males showed a generalized suppression of HPA, SAM system and cardiovascular markers following both stress and cue, SA women demonstrated a selective sympatho-adrenal suppression to stress only and an enhanced HPA response to both stress and cue. These gender variations are discussed in terms of their potential impact on relapse vulnerability and treatment outcome.
Aims: The study used an animal model of fetal alcohol spectrum disorders (FASD) to investigate the impact of alcohol exposure during a period equivalent to all three trimesters in humans on social recognition memory. It was hypothesized that the effects on specific aspects of social recognition memory would be sexually dimorphic. Methods: This study exposed rats to ethanol during both the prenatal and early postnatal periods. Two control groups included a group exposed to the administration procedures but not ethanol and a non-treated group. At ∼90 days, all rats were tested repeatedly in a test of social recognition memory with a juvenile animal of the same sex. Experimental rats of both sexes were allowed to investigate an unknown juvenile for either 2, 3 or 5 min and then, after a delay of 30, 60, 120 and 180 min, were allowed to investigate the same juvenile for 5 min. Results: Male rats investigated the juvenile for much longer than female rats. Ethanol-exposed male rats showed a deficit in recognition memory that was evident with longer delays when the initial investigation time was either 2- or 3-min long. In contrast, ethanol-exposed female rats showed a deficit in recognition memory only when the initial investigation period was of 2 min. Measurement of oxytocin receptor binding in the amygdala region indicated that ethanol exposure lowered oxytocin receptor binding in females but not males. Conclusions: The results suggest that ethanol exposure during development caused a deficit in memory duration but not encoding in males and a deficit in encoding but not memory duration in females. The deficit in ethanol-exposed females may be related to changes in oxytocin receptors in the amygdala.
Aims: We have found consistent and significant sex differences in recovery from the increased seizure susceptibility observed during ethanol withdrawal (EW) in our rat model system. The main objective of the present study was to determine if sex differences in EW generalized to an additional behavioral measure startle reactivity. Methods: Acoustic startle or seizure threshold responses were measured in separate groups of rats at 1 day or 3 days of EW. Results: Both pair-fed control and EW males showed greater increases in acoustic startle responses than either the female or ovariectomized female (OVX) counterparts. There was a selective effect of pregnanolone on acoustic startle in that it reduced peak force of response only at 3 days EW in male rats. Unexpectedly, it modestly increased startle reactivity in control female and OVX rats. Acute treatment with low-dose ethanol trended toward reducing startle responses in control animals, as expected, while generally enhancing startle responses during EW. All sex conditions showed an enhanced startle response during EW following administration of the higher dose of estradiol compared to control animals. Estradiol did not alter seizure thresholds in control animals. However, it was anticonvulsant for males at 3 days EW, females and OVX at 1 day EW. Conclusions: Observed sex differences in the startle reactivity during EW were consistent with earlier findings comparing EW seizure risk in male and female rats. Responses of OVX suggested that both hormones and differences in brain structures between males and females have a role in these sex differences. Our findings add weight to recommendations that treatment of alcohol withdrawal in humans should consider hormonal status as well as withdrawal time.
Aims: Caffeine is a central nervous system stimulant that produces its primary effects via antagonism of the A1 and A2A adenosine receptor subtypes. Previous work demonstrated a sex difference in neurotoxicity produced by specific adenosine A1 receptor antagonism during ethanol withdrawal (EWD) in vitro that was attributable to effects downstream of A1 receptors at NMDA receptors. The current studies were designed to examine the effect of non-specific adenosine receptor antagonism with caffeine during ethanol withdrawal on hippocampal toxicity in cultures derived from male and female rats. Methods: At 5 days in vitro (DIV), half of the male and female organotypic hippocampal slice cultures were exposed to 50 mM ethanol (EtOH) in culture media for 10 days before exposure to caffeine (5, 20 and 100 μM) for the duration of a 24 h EWD period. In keeping with this timeline, the remaining ethanol-naïve cultures were given media changes at 10 and 15 DIV and exposed to caffeine (5, 20 and 100 μM) for 24 h at 15 DIV. Cytotoxicity was assessed by fluorescent microscopy and quantification of propidium iodide (PI) uptake in the pyramidal cell layers of the CA1 and CA3 regions and the granule cell layer of the dentate gyrus (DG). A two-way (sex × treatment) ANOVA was conducted within each hippocampal region. Results: Twenty-four-hour withdrawal from 10-day exposure to 50 mM ethanol did not produce increased PI uptake in any hippocampal region. Caffeine exposure (5, 20 and 100 μM) in ethanol-naïve cultures did not produce toxicity in the DG or CA1 region, but 20 μM caffeine produced modest toxicity in the CA3 region. Exposure to 20 μM caffeine during EWD produced cytotoxicity in all hippocampal regions, though toxicity was sex-dependent in the DG and CA1 region. In the DG, both 5 and 20 μM caffeine produced significantly greater PI uptake in ethanol-exposed female cultures compared to ethanol-naïve female cultures and all male cultures. Similarly, 20 μM caffeine caused markedly greater toxicity in female cultures as compared to male cultures in the CA1 region. Conclusions: Twenty-four-hour exposure to caffeine during EWD produced significant toxicity in the pyramidal cell layer of the CA3 region in male and female cultures, though toxicity in the granule cell layer of the DG and pyramidal cell layer of the CA1 region was observed only in female cultures. Greater sensitivity of the female slice cultures to toxicity upon caffeine exposure after prolonged ethanol exposure is consistent with previous studies of effects of a specific A1 receptor antagonism during EWD on toxicity and indicate that this effect is independent of the hormonal milieu. Together, these data suggest that the A1 receptor subtype is predominant in mediating caffeine's neurotoxic effects during EWD. These findings demonstrate the importance of considering gender/sex when examining neuroadaptive changes in response to ethanol exposure and withdrawal.
Aims: Considerable laboratory research indicates that moderate doses of alcohol impair a broad range of skilled activities related to driving performance in young adults. Although laboratory studies show that the intensity of impairment is generally dependent on the blood alcohol concentration, some reviews of this literature suggest that women might be more sensitive to the impairing effects of alcohol than men. The present study tested this hypothesis. Methods: Drawing on data from previous experiments in our laboratory, we compared men and women in terms of the degree to which a challenge dose of alcohol (0.65 g/kg) impaired their simulated driving performance and measures of three separate behavioral and cognitive functions important to driving performance: motor coordination, speed of information processing and information-processing capacity. Results: Alcohol significantly impaired all aspects of performance. Moreover, women displayed greater impairment than men on all behavioral tests and also reported higher levels of subjective intoxication compared with men. Conclusions: Both biological and social–cultural factors have been implicated in gender differences in the behavioral responses to alcohol. The current evidence of heightened sensitivity to alcohol in women highlights the need for better understanding the biological and environmental factors underlying this gender difference.
Aims: This study examines whether the severity of baseline alcohol consumption/consequences moderates the effect of an alcohol brief intervention (BI) in the emergency department (ED). Methods: Injured patients (N = 494) were recruited from an ED, randomly assigned to receive brief advice or not and completed a 12-month follow-up interview. Results: A significant interaction was found between severity of baseline alcohol consumption (i.e. average weekly, binge drinking) and receipt of a BI on alcohol consumption at 12 months. The form of this interaction indicates that the BI group tended to report lower alcohol consumption at follow-up than the untreated group especially in those who had reported high baseline consumption. Severity of alcohol consequences at baseline did not significantly impact the effect of the BI on 12-month outcomes. Conclusion: ED patients with higher alcohol consumption benefit from BI. In some cases, the BI's effects may be enhanced for patients who are heavier drinkers, perhaps due to a greater opportunity to develop a discrepancy between current behavior and future goals.
Aims: The goal of this preliminary study was to evaluate the relationship between blood phosphatidylethanol (PEth) and recent drinking in patients with liver disease and hypertension. Methods: Twenty-one patients with liver disease and 21 patients with essential hypertension were recruited at an academic medical center. Alcohol consumption was estimated using validated self-report methods, and blood PEth was measured by HPLC-MS/MS at a contracted laboratory. Nonparametric comparisons were made between abstainers/light drinkers, moderate drinkers consuming between 1 and 3 drinks per day, and those drinking above this level. Regression methods were used to estimate the effects of liver disease, gender, and age on the relationship between PEth and alcohol use, and to estimate the strength of the linear relationship between PEth and drinking. Results: PEth differed significantly between the three drinking groups (P < 0.001). The relationship between PEth and alcohol did not differ between hypertension and liver disease patients (P = 0.696), nor by gender and age. While there was substantial variability between subjects in the PEth concentration given a similar level of reported drinking, the amount of ethanol consumed was strongly associated with the PEth concentration (P < 0.001). Conclusion: Results support PEth measurement by HPLC-MS/MS as a promising marker of past 1- to 2-week moderate to heavy alcohol consumption in patients with and without liver disease. PEth appears useful for differentiating abstinence or light drinking from moderate to heavy consumption, but may have limited utility for differentiating moderate from heavy alcohol use.
Aims: The aims of this study were (1) to examine the association between neighborhood alcohol outlet density and individual self-reported alcohol-related health outcomes in the last year—sexually transmitted infections (STI), motor vehicle accidents, injury, liver problems, hypertension and experienced violence; (2) to determine whether the relationship between morbidity and alcohol outlet density is mediated by individual alcohol consumption; and (3) to explore the role of alcohol outlet density in explaining any observed racial and ethnic differences in morbidity. Method: Hierarchical models from a random sample of Los Angeles, CA, and Louisiana residents (N = 2881) from 217 census tracts were utilized. The clustering of health and social outcomes according to neighborhood varied by health problem examined. Results: There was substantial clustering of STI (intraclass correlation coefficient, ICC = 12.8%) and experienced violence (ICC = 13.0%); moderate clustering of liver problems (ICC = 3.5%) and hypertension (ICC = 3.9%); and low clustering of motor vehicle accident (ICC = 1.2%) and injury (ICC = 1.4%). Alcohol outlet density was significantly and positively associated with STI (crude OR = 1.80, 95% CI = 1.10–3.00), liver problems (crude OR = 1.33, 95% CI = 1.02–1.75) and experienced violence (crude OR = 1.31, 95% CI = 1.13–1.51) although not with other morbidity outcomes. Mediation analyses of morbidity outcomes revealed partial mediation of individual alcohol consumption in the relationship between alcohol density and STI and violence, and full mediation for liver problems. Conclusions: Findings support the concept that off-premise alcohol outlets in the neighborhood environment may impact health and social outcomes, either directly or indirectly, through individual alcohol consumption and these associations may be heterogeneous with respect to race and ethnicity.
Aims: The present study sought to investigate the relationship between the HPA axis reactivity to stress, the endogenous opioid system and stress-induced drinking behavior. Methods: In the present study, 74 non-treatment-seeking alcohol-dependent subjects were tested under two mood conditions, neutral and stress, in separate testing sessions. Salivary cortisol measurements were obtained following stress induction and during the neutral control condition. Multiple measurements of alcohol intake, latency to access the alcohol cue and craving for alcohol were obtained during cue-availability testing. In addition, 52 of the study subjects were genotyped for the μ-opioid receptor. Results: A blunted cortisol response to stress was significantly correlated with increased alcohol intake following stress exposure compared to alcohol intake during the neutral session. There was not a clear correlation between the change in cortisol in response to stress and the change in latency to access alcohol or alcohol craving in response to stress. Carriers of the Asp40 variant of the μ-opioid receptor exhibited a dampened cortisol response to stress, higher alcohol intake and greater craving in response to stress compared to Asn40 homozygotes, although these differences were not statistically significant. Conclusions: The results of the present study indicate that a blunted biological stress response was correlated with increased drinking in response to stress. The Asp40 variant of the μ-opioid receptor may be associated with this HPA axis hyporeactivity although the small sample size used in the present study did not permit adequate evaluation of this association.
Aims: Studies have yielded conflicting results regarding alcohol's influence on HIV outcomes, particularly after highly active antiretroviral treatment (HAART). Discrepant findings may be related to confounding variables, including gender, patterns of alcohol abuse and type of alcohol beverage beyond the amount consumed. Methods: Using a cohort study, differences in HAART effectiveness after 24 weeks of therapy were compared as a function of amount and preference for alcohol, drinking only liquor (LI, n = 55) or only wine or beer (BW, n = 110). Given the critical role of thymus on HAART response, changes in thymus size, CD4s, naïve lymphocytes and viral loads were assessed. Results: After HAART, positive increases in both CD4s (+12 cell counts/mm3) and thymus size (+0.7 mm3) were evident in the BW group. In contrast, the LI subgroup exhibited a decline in both parameters (−4 CD4 cells/mm3 and −0.6 mm3 in thymus size). Women in the LI group exhibited significantly lower CD4 (163.4 ± 46.2) and naïve counts (178 ± 69.5) than LI men (CD4: 281.6 ± 203, P = 0.05; lymphocytes: 301.4 ± 198, P = 0.04). In adjusted regression models, the LI compared to the BW subgroup had greater odds of maintaining detectable viral loads (RR = 1.35, 95% CI 1.04–1.75; P = 0.03), increased thymus volumes (RR = 3.8, P = 0.04) and replenished naïve cells (RR = 13, P = 0.02). Conclusions: Liquor was associated with thymus deterioration and thus with poorer viro-immune outcomes after HAART. Subtyping participants by alcohol consumption patterns seems to be clinically relevant and needs to be accounted for in future studies.
Aims: Conventional tests for alcohol dependence often fail to detect hazardous and harmful alcohol use (HHAU) accurately. We previously validated the Bayesian Alcoholism Test (BAT) for the detection of HHAU among males. This uses 15 biochemical and clinical variables, including questionnaire data to calculate the probability of harmful (>80 g alcohol/day), hazardous (40–80 g/day) and ‘moderate’ (<40 g/day) drinking. Here we investigate the BAT's diagnostic performance when more limited clinical data are available. Methods: The WHO/ISBRA Collaborative Project recruited subjects from the general community and alcohol dependence treatment services. We analysed data from male drinkers: 318 alcohol dependent, 220 heavy and 712 moderate drinkers. Drinking was assessed using the Alcohol-Use Disorders and Associated Disabilities Interview Schedule. Eight of 15 markers used in the original BAT could be extracted from the WHO/ISBRA dataset. Results: Comparing harmful to moderate drinkers, the area under the ROC curve for BAT (0.90) was significantly higher than that for CDT (0.82), GGT (0.77) and AST (0.76). Comparing hazardous to moderate drinkers, the area under the ROC curve for BAT (0.78) was significantly higher than that for AST (0.65) but not significantly higher than that for CDT (0.71) and GGT (0.70). For all 1250 subjects, the amount consumed correlated significantly better with BAT (0.65) than with CDT (0.52), GGT (0.44) or AST (0.40) alone. Conclusions: The BAT is more accurate than commonly used single biological markers in detecting harmful alcohol use, even when only half the input requirements are available. Computerized record keeping increases the practicality of use of algorithms in the detection of harmful drinking.
Aims: To investigate the relationship between the sweet liking/sweet disliking phenotype (a putative probe of brain opioid function), craving for alcohol and response to treatment with naltrexone in individuals with alcohol dependence. Methods: Forty individuals with alcohol dependence were enrolled in a 12-week open-label study of 50 mg of naltrexone with four sessions of motivational enhancement therapy. Prior to treatment, individuals completed a sweet preference test and the Penn Alcohol Craving Scale. Subjects were categorized as sweet liking (SL), n = 15, or sweet disliking (SDL), n = 25, via a standard sweet tasting paradigm. The sweet tasting results were blinded to the subjects and to treatment staff. SL status, pretreatment craving and their interaction were examined as predictors of frequency of abstinent days and heavy drinking days during treatment with naltrexone. Results: SL and SDL subjects achieved similar reductions in percent heavy drinking days with treatment. During treatment, SDL subjects had 48% abstinent days compared to 30% for SL subjects (P = 0.034). Pretreatment craving did not predict % heavy drinking days or % abstinent days. An interaction effect was found between the SL/SDL phenotype and pretreatment craving such that SL subjects with high craving demonstrated higher rates of percent abstinent days whereas SDL subjects with high craving demonstrated lower rates of percent abstinent days, P < 0.001. Conclusions: These findings indicate that the SL/SDL phenotype may predict variation in response to naltrexone and/or counseling treatment. Furthermore, the SL/SDL phenotype may interact with craving to provide a more robust prediction of outcome with naltrexone or counseling.
Aims: We have previously suggested that acute ethanol consumption by normal subjects decreases the availability of circulating tryptophan (Trp) to the brain by activating liver Trp pyrrolase, the first and rate-limiting enzyme of the (major) kynurenine pathway of Trp degradation. The aim of the present study was to examine this hypothesis further by measuring plasma levels of kynurenine metabolites following alcohol consumption. Methods: After an overnight fast and a light breakfast, each of 10 healthy subjects received one of five drinks (placebo and doses of ethanol of 0.2, 0.4, 0.6 and 0.8 g/kg body weight in tonic water) on five different occasions. Blood samples were withdrawn 2 h later and plasma was analysed for concentrations Trp, competing amino acids (CAA) and kynurenine metabolites. Results: Along with the depletion of plasma Trp and the decrease in its availability to the brain, as expressed by the ratio of [Trp]/[CAA], plasma kynurenine was elevated by doses of ethanol of 0.2–0.8 g/kg body weight. The ratio% of [kynurenine]/[Trp], an index of the expression of Trp pyrrolase activity, was also increased by all doses of ethanol. Conclusions: We conclude that activation of liver Trp pyrrolase mediates the depletion of plasma Trp and the decrease in its availability to the brain induced by acute ethanol consumption.
The term ‘Foetal Alcohol Spectrum Disorders (FASD)’ refers to the range of disabilities that may result from prenatal alcohol exposure. This article reviews the effects of ethanol on the developing brain and its long-term structural and neurobehavioural consequences. Brain imaging, neurobehavioural and experimental studies demonstrate the devastating consequences of prenatal alcohol exposure on the developing central nervous system (CNS), identifying specific brain regions affected, the range of severity of effects and mechanisms involved. In particular, neuroimaging studies have demonstrated overall and regional volumetric and surface area reductions, abnormalities in the shape of particular brain regions, and reduced and increased densities for white and grey matter, respectively. Neurobehaviourally, FASD consists of a continuum of long-lasting deficits affecting multiple aspects of cognition and behaviour. Experimental studies have also provided evidence of the vulnerability of the CNS to the teratogenic effects of ethanol and have provided new insight on the influence of risk factors in the type and severity of observed brain abnormalities. Finally, the potential molecular mechanisms that underlie the neuroteratological effects of alcohol are discussed, with particular emphasis on the role of glial cells in long-term neurodevelopmental liabilities.
Aims: The present experiments examined sex differences in ethanol intake and in the influence of a social context on aversive properties of ethanol in adolescent and adult Sprague-Dawley rats. Methods: Experiment 1 examined ethanol intake, with animals receiving daily 2-h access to ethanol and water for 8 days. Experiment 2 assessed the aversive effects of ethanol using a conditioned taste aversion (CTA) paradigm, with animals placed either alone or with a same-sex, same-age peer during the ethanol intoxication phase of conditioning. Results: Ethanol intake varied with both age and sex, although the sex differences emerging at each age were opposite in nature. Adolescent males consumed more ethanol relative to their body weights than adolescent females and adults of both sexes, whereas adult females generally consumed more than adult males. The CTA test revealed no sex differences in aversive effects of ethanol in adults, whereas adolescent males were less sensitive to the aversive properties of ethanol than adolescent females when intoxication occurred in the presence of a peer. Ethanol-induced CTA was evident in adults at lower doses than in adolescents. Conclusions: These results suggest that age differences in ethanol intake in males and sex differences in intake during adolescence may be associated in part with the relative insensitivity of the male adolescents to ethanol's aversive properties, especially when intoxication occurred in a social context. However, the elevated ethanol intake observed in adult females relative to their male counterparts appears to be unrelated to the aversive properties of ethanol.
The Paddington Alcohol Test (PAT) has evolved over 15 years as a clinical tool to facilitate emergency physicians and nurses giving brief advice and the offer of an appointment for brief intervention by an alcohol nurse specialist. Previous work has shown that unscheduled emergency department re-attendance is reduced by ‘making the connection’ between alcohol misuse and resultant problems necessitating emergency care. The revised ‘PAT (2009)’ now includes education on clinical signs of alcohol misuse and advice on when to request a blood alcohol concentration.