Aims: This study aims to determine the impact of Screening, Brief Intervention and Referral for Treatment (SBIRT) in reducing alcohol consumption in emergency department (ED) patients at 3, 6, and 12 months following exposure to the intervention. Methods: Patients drinking above the low-risk limits (at-risk to dependence), as defined by National Institute of Alcohol Abuse and Alcoholism (NIAAA), were recruited from 14 sites nationwide from April to August 2004. A quasi-experimental comparison group design included sequential recruitment of intervention and control patients at each site. Control patients received a written handout. The Intervention group received the handout and participated in a brief negotiated interview with direct referral for treatment if indicated. Follow-up surveys were conducted at 3, 6, and 12 months by telephone using an Interactive Voice Response (IVR) system. Results: Of the 1132 eligible patients consented and enrolled (581 control, 551 intervention), 699 (63%), 575 (52%) and 433 (38%) completed follow-up surveys via IVR at 3, 6, and 12 months, respectively. Regression analysis adjusting for the clustered sampling design and using multiple imputation procedures to account for subject attrition revealed that those receiving SBIRT reported roughly three drinks less per week than controls (B = −3.00, SE = 1.06, P < 0.05) and the level of maximum drinks per occasion was approximately three-fourths of a drink less than controls (B = -0.76, SE = 0.29, P < 0.05) at 3 months. At 6 and 12 months post-intervention, these effects had weakened considerably and were no longer statistically or substantively significant. Conclusion: SBIRT delivered by ED providers appears to have short-term effectiveness in reducing at-risk drinking, but multi-contact interventions or booster programs may be necessary to maintain long-term reductions in risky drinking.

Aims: Heavy drinkers tend to overestimate how much others drink (normative fallacy), at least in college samples. Little research has been conducted to evaluate whether normative misperceptions about drinking extend beyond the college population. The present study explored normative misperceptions in an adult general population sample of drinkers. Methods: As part of a larger study, in Toronto, Canada, a random digit dialling telephone survey was conducted with 14,009 participants who drank alcohol at least once per month. Respondents with Alcohol Use Disorders Identification Test of eight or more (n = 2757) were asked to estimate what percent of Canadians of their same sex: (a) drank more than they do; (b) were abstinent and (c) drank seven or more drinks per week. Respondents' estimates of these population drinking norms were then compared with the actual levels of alcohol consumption in the Canadian population. Results: A substantial level of normative misperception was observed for estimates of levels of drinking in the general population. Estimates of the proportion of Canadians who were abstinent were fairly accurate. There was some evidence of a positive relationship between the respondents' own drinking severity and the extent of normative misperceptions. Little evidence was found of a relationship between degree of normative misperceptions and age. Conclusion: Normative misperceptions have been successfully targeted in social norms media campaigns as well as in personalized feedback interventions for problem drinkers. The present research solidifies the empirical bases for extending these interventions more widely into the general population.

Aims: The aims were to provide proofs of mechanism and principle by establishing the ability of kynurenine metabolites to inhibit the liver mitochondrial low Km aldehyde dehydrogenase (ALDH) activity after administration and in vivo, and to induce aversion to alcohol. Methods: Kynurenic acid (KA), 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3-HAA) were administered to normal male Wistar rats and ALDH activity was determined both in vitro in liver homogenates and in vivo (by measuring blood acetaldehyde following ethanol administration). Alcohol consumption was studied in an aversion model in rats and in alcohol-preferring C57 mice. Results: ALDH activity was significantly inhibited by all three metabolites by doses as small as 1 mg/kg body wt. Blood acetaldehyde accumulation after ethanol administration was strongly elevated by KA and 3-HK and to a lesser extent by 3-HAA. All three metabolites induced aversion to alcohol in rats and decreased alcohol preference in mice. Conclusions: The above kynurenine metabolites of tryptophan induce aversion to alcohol by inhibiting ALDH activity. An intellectual property covering the use of 3-HK and 3-HAA and derivatives thereof in the treatment of alcoholism by aversion awaits further development.

Aims: The aims were to provide proofs of mechanism and principle by establishing the ability of the amino acid L-tryptophan (Trp) combined with the kynureninase inhibitor benserazide (BSZ) to inhibit the liver mitochondrial low Km aldehyde dehydrogenase (ALDH) activity after administration and in vivo and to induce aversion to alcohol. Methods: Trp, BSZ or both were administered to male Wistar rats and ALDH activity was determined both in vitro in liver homogenates and in vivo (by measuring acetaldehyde accumulation in blood after ethanol administration). Alcohol consumption was studied in an aversion model in rats and in alcohol-preferring C57 mice. Results: Combined administration of Trp + BSZ, but neither compound alone, produced a strong inhibition of ALDH activity and an increase in blood acetaldehyde concentration after ethanol, and induced aversion to alcohol in rats and decreased preference in mice. Another kynureninase inhibitor, carbidopa, induced aversion to alcohol by itself, which was reversed by Trp co-administration. Conclusions: The present results establish a prior art for the use of a combination of Trp plus BSZ in the treatment of alcoholism by aversion, which merits rapid clinical development.

Aim: This functional magnetic resonance imaging (fMRI) study examined reactivity to alcohol, polydrug, marijuana and emotional picture cues in students who were referred to a college alcohol and drug assistance program. Methods: The fMRI data of 10 participants (5 females; 5 males) were collected while they viewed standardized emotional and appetitive cues. Results: Positive and negative emotional cues produced greater activity than neutral cues in the expected brain areas. Compared with neutral cues, alcohol cues produced greater brain activation in the right insula, left anterior cingulate, left caudate and left prefrontal cortex (Z = 2.01, 1.86, 1.82, 1.81, respectively; P < 0.05). Drug cues produced significantly greater left prefrontal activity compared with neutral cues, with polydrug cues activating the right insula and marijuana cues activating left anterior cingulate. Conclusions: Students at-risk for alcohol abuse showed neural reactivity to alcohol cues in four brain regions, which is consistent with their greater use of alcohol. Insula activation to appetitive cues may be an early marker of risk for progression to alcohol/drug abuse.

Aims: This study examined brain activity using functional magnetic resonance imaging (fMRI) and reaction time (RT) during an implicit repetition priming memory task involving alcohol, polydrug, marijuana and emotional picture cues. Methods: Participants were 5 male and 5 female high-risk college students who had just participated in a cue exposure study (Ray et al., this issue). fMRI and RT data were collected while participants made decisions about previously seen and new picture cues. Results: Both behavioral RT and brain imaging data revealed strong memory priming for drug and alcohol cues. Neurologically, a repetition priming effect (suppression in neural activity for repeated cues) was observed in response to alcohol cues in the left prefrontal, bilateral occipital, and bilateral occipitotemporal regions, as well as right insula and right precuneus (Z ranged from 3.03 to 3.31 P < 0.05). Polydrug cues elicited priming in the occipital and temporal areas, and marijuana cues in the occipital area. Conclusions: Prefrontal and insular cortex involvement both in reactivity to alcohol cues (Ray et al., this issue) and subsequent implicit memory processing of these cues, as found in this study, suggests their potential role in the maintenance of high-risk alcohol use behaviors.

Aims: Our overall objective was to examine whether characteristics of epithelial lining fluid (ELF) from subjects with alcohol use disorders (AUDs) obtained via bronchoalveolar lavage (BAL) contribute to their predisposition to pneumococcal pneumonia. We sought to compare the anti-pneumococcal activity of acellular human BAL from subjects with AUDs to matched controls. Further, differences in BAL lysozyme activity and lactoferrin concentrations between these two groups were examined to determine the effect of AUDs on these antimicrobial proteins. Methods: BAL was performed in subjects with AUDs and matched controls. Acellular BAL was used at varying concentrations in an in vitro killing assay of Streptococcus pneumoniae, type 2, and the percent kill of organisms per microgram per milliliter total BAL protein was ascertained. Lysozyme activity and lactoferrin concentrations were measured in BAL from subjects and controls at measured concentrations of BAL protein. Results: AUD subjects (n = 15) and controls (n = 10) were enrolled in these investigations who were balanced in terms of smoking history. Using a mixed effect model, across the range of BAL protein concentrations, killing of pneumococcus tended to be less potent with BAL fluid from AUD subjects. Additionally, lysozyme activity and lactoferrin concentrations were significantly lower in the AUD group. Conclusions: The predisposition for pneumococcal pneumonia among those with AUDs may be in part mediated through effects of alcohol on substances within ELF that include antimicrobial proteins. Clarifying the composition and activity of ELF antimicrobial proteins in the setting of AUDs via investigations with human BAL fluid can help establish their contribution to the susceptibility for pulmonary infections in these individuals.

Aims: The aims of this study were to study whether alcohol-related self-reported problems follow the same pattern of changes in alcohol consumption in southern Sweden, assumed to be affected by a decrease in Danish spirits tax and by an increase in Swedish travellers’ import quotas, and to study whether the results obtained for southern and northern Sweden follow the predictions of Skog's theory of collectivity of drinking cultures. Methods: Analysis was carried out on a sample from the  Swedish general population from southern and northern Sweden separately. Two indices such as impaired self-control/dependent behaviour and extrinsic problems for alcohol-related problems were computed and analysed in terms of sex, age, income and alcohol consumption level. Results: Although there were no huge changes in the number of persons reporting alcohol-related problems, the general trend in data for various subpopulations was a decrease in the southern site and an increase in the northern site. In the northern site, the increase in alcohol consumption among men also showed an increase in alcohol-related problems. However, various population subgroups changed in different directions and did not move in concert over the population distribution. Conclusions: Analysis confirmed that alcohol-related problems, according to the two indices used, followed a similar pattern to alcohol consumption, but less divergent. A version of Skog's theory applied on alcohol-related problems could not confirm that alcohol-related problems did not change collectively within the population.

Aims: To investigate the relationship between socio-demographic factors and alcohol drinking patterns identified through a formal analysis of the factor structure of the Alcohol Use Disorders Identification Test (AUDIT) score in a population sample of working-age men in Russia. Methods: In 2008–2009, a sample of 1005 men aged 25–59 years living in Izhevsk, Russia were interviewed and information collected about socio-demographic circumstances. Responses to the AUDIT questions were obtained through a self-completed questionnaire. Latent dimensions of the AUDIT score were determined using confirmatory factor analysis and expressed as standard deviation (SD) units. Structural equation modelling was used to estimate the strength of association of these dimensions with socio-demographic variables. Results: The AUDIT was found to have a two-factor structure: alcohol consumption and alcohol-related problems. Both dimensions were higher in men who were unemployed seeking work compared with those in regular paid employment. For consumption, there was a difference of 0.59 SDs, (95% confidence interval (CI): 0.23, 0.88) and for alcohol-related problems one of 0.66 SD (95% CI: 0.31, 1.00). Alcohol-related problems were greater among less educated compared with more educated men (P-value for trend = 0.05), while consumption was not related to education. Similar results were found for associations with an amenity index based on car ownership and central heating. Neither dimension was associated with marital status. While we found evidence that the consumption component of AUDIT was underestimated, this did not appear to explain the associations of this dimension with socio-demographic factors. Conclusions: Education and amenity index, both measures of socio-economic position, were inversely associated with alcohol-related problems but not with consumption. This discordance suggests that self-reported questions on frequency and volume may be less sensitive markers of socio-economic variation in drinking than are questions about dependence and harm. Further investigation of the validity of the consumption component of AUDIT in Russia is warranted as it appears that the concept of a standard ‘drink’ as used in the instrument is not understood.

Aims: Dangerous alcohol consumption practices are common in adolescents, yet little is known about their consequences on attainment of peak bone mass and long-term skeletal integrity. We previously demonstrated that binge alcohol-exposed adolescent rats showed site-specific reductions in accruement of bone mineral density and bone strength, which were incompletely recovered following prolonged alcohol abstinence. Currently, we analysed the vertebral transcriptome of adolescent rats following alcohol treatment and abstinence to identify long-term molecular changes in the lumbar spine. Methods: Sixty male adolescent Sprague-Dawley rats were assigned to one of six treatment groups receiving binge alcohol (3 g/kg) or saline i.p., 3 consecutive days (acute binge), 4 consecutive weekly (3-day) binge cycles (chronic binge) or 4 weekly binge cycles followed by a 30-day abstinence period (chronic binge with abstinence). Following treatment, lumbar vertebrae were assayed for global transcriptional changes using gene array technology. Results: Analysis of the adolescent rat vertebral transcriptome identified clusters of binge alcohol-sensitive genes displaying differential expression patterns starting before bone damage was seen and persisting after alcohol treatment was discontinued. Functional grouping of these gene clusters identified candidate cellular pathways affected following acute and chronic binge treatment, as well as pathways remaining modulated following abstinence. Conclusions: These results demonstrate that binge alcohol exposure can produce disruptions of normal bone gene expression patterns in the adolescent rat that persist well beyond the period of active intoxication. This data may have relevance to peak bone mass attainment and future risk of skeletal disease in adolescents engaging in repeated binge-drinking episodes.

Aims: To ascertain the views of general practitioners (GPs) regarding the prevention and management of alcohol-related problems in practice, together with perceived barriers and incentives for this work; to compare our findings with a comparable survey conducted 10 years earlier. Methods: In total, 282 (73%) of 419 GPs surveyed in East Midlands, UK, completed a postal questionnaire, measuring practices and attitudes, including the Shortened Alcohol and Alcohol Problems Perception Questionnaire (SAAPPQ). Results: GPs reported lower levels of post-graduate education or training on alcohol-related issues (<4 h for the majority) than in 1999 but not significantly so (P = 0.031). In the last year, GPs had most commonly requested more than 12 blood tests and managed 1–6 patients for alcohol. Reports of these preventive practices were significantly increased from 1999 (P < 0.001). Most felt that problem or dependent drinkers' alcohol issues could be legitimately (88%, 87%) and adequately (78%, 69%) addressed by GPs. However, they had low levels of motivation (42%, 35%), task-related self-esteem (53%, 49%) and job satisfaction (15%, 12%) for this. Busyness (63%) and lack of training (57%) or contractual incentives (48%) were key barriers. Endorsement for government policies on alcohol was very low. Conclusion: Among GPs, there still appears to be a gap between actual practice and potential for preventive work relating to alcohol problems; they report little specific training and a lack of support. Translational work on understanding the evidence-base supporting screening and brief intervention could incentivize intervention against excessive drinking and embedding it into everyday primary care practice.

Aims: In this study, we tested the impact of pretreatment with alcohol on subsequent alcohol drinking in outbred Sprague–Dawley and selectively bred alcohol-preferring (P) rats. Methods: As a pretreatment, male Sprague–Dawley and P rats were given a passive oral administration of either alcohol (1.0 g/kg) or tap water. Then, they were given free choice of drinking alcohol (5% v/v) or water in their home cages, which was measured over 4 weeks. Results: Without alcohol pretreatment, there was no significant strain difference in alcohol preference; both strains preferred 5% (v/v) alcohol solution. The strain difference was only apparent in the groups given alcohol pretreatment. This arose from the fact that alcohol pretreatment significantly reduced alcohol preference in the Sprague–Dawley rats to a level well below 50%, while it did not alter drinking behavior in P rats. The same effects were seen with total alcohol consumption (g/kg/day). These effects persisted throughout the 4 weeks of the study. Conclusions: The principal difference between the Sprague–Dawley and P rats was that the P rats did not show the normal aversion to alcohol after forced exposure to alcohol that the Sprague–Dawley rats showed. One of the potential contributors to high alcohol intake and preference in P rats may be lack of sensitivity to aversive effects of alcohol.

Aims: To examine whether individual changes in alcohol consumption among female alcoholics under treatment are predicted by level of and changes in depression and dysfunctional attitudes. Method: A total of 120 women who were treated for alcohol addiction at the Karolinska Hospital in Stockholm (Sweden) were assessed twice over a 2-year period using the Depression scale from the Symptom Checklist-90, the Alcohol Use Inventory and the Dysfunctional Attitude Scale (DAS). Latent growth curve analysis was used. Results: Decrease in alcohol consumption, depression and dysfunctional attitude variables were found at group level. The results also showed significant individual variation in change. Changes in alcohol consumption were predicted by baseline alcohol drinking, as well as by level and changes in depression. Stronger reduction in depression was related to higher level of depression at baseline, and with reduction in dysfunctional attitudes. Different DAS sub-scales resulted in different magnitude of the model relations. Good treatment compliance was related to lower baseline level in depression, but also with higher baseline level in dysfunctional attitudes, and predicted stronger reduction in alcohol consumption. Conclusion: This paper shows the importance of incorporating both individual level and change in depression as predictors of change in alcohol consumption among subjects treated for alcohol addiction. Also, dysfunctional attitudes are both indirectly and directly related to treatment outcome. By incorporating alcohol consumption, depression and dysfunctional attitudes as targets of intervention, treatment compliance and outcome may be enhanced.

Aims: The study aimed to determine whether alcohol use during late adolescence contributes to the weight gain from adolescence to young adulthood or risk of obesity or waist circumference at young adulthood.

Methods: A population-based, longitudinal study of 5563 Finnish twins born in 1975–1979 and surveyed at ages 16 (T1), 17 (T2), 18 (T3) and 23–27 (T4) years. Drinking habits, height and weight were self-reported at T1, T2, T3 and T4; waist circumference was self-measured at T4. As potential confounders, we used smoking, diet, physical activity, place of residence, socio-economic status and parents' body mass index (BMI).

Results: Compared to the reference group (drinking once to twice per month), the BMI increase from T3 to T4 was less among abstaining men (−0.62 kg/m2, (95% CI −1.04, −0.20)) and among women in those drinking less than monthly (−0.38 kg/m2, (−0.71, −0.04)). In women, at least weekly drinking was associated with larger waist circumference (Beta 1.55 cm, (0.48, 2.61)), but this became statistically non-significant after adjusting for potential confounders. In a multilevel model for change, drinking frequency was not associated with weight change in women; in men, a negative association was seen, but it was statistically non-significant after adjusting for potential confounders.

Conclusions: These results from a population-based study with a large set of confounding variables suggest that alcohol use during adolescence has at most a minor effect on weight gain or development of abdominal obesity from adolescence to young adulthood.

Aims: To review the patterns, contexts and impacts of alcohol use associated with commercial sex reported in the global literature. Methods: We identified peer-reviewed English-language articles from 1980 to 2008 reporting alcohol consumption among female sex workers (FSWs) or male clients. We retrieved 70 articles describing 76 studies, in which 64 were quantitative (52 for FSWs, 12 for male clients) and 12 qualitative. Results: Studies increased over the past three decades, with geographic concentration of the research in Asia and North America. Alcohol use was prevalent among FSWs and clients. Integrating quantitative and qualitative studies, multilevel contexts of alcohol use in the sex work environment were identified, including workplace and occupation-related use, the use of alcohol to facilitate the transition into and practice of commercial sex among both FSWs and male clients, and self-medication among FSWs. Alcohol use was associated with adverse physical health, illicit drug use, mental health problems, and victimization of sexual violence, although its associations with HIV/sexually transmitted infections and unprotected sex among FSWs were inconclusive. Conclusions: Alcohol use in the context of commercial sex is prevalent, harmful among FSWs and male clients, but under-researched. Research in this area in more diverse settings and with standardized measures is required. The review underscores the importance of integrated intervention for alcohol use and related problems in multilevel contexts and with multiple components in order to effectively reduce alcohol use and its harmful effects among FSWs and their clients.

Aims: To compare the mortality of female alcoholics randomly assigned to the woman-only programme ‘Early treatment for Women with Alcohol Addiction’ (EWA) versus those who received mixed gender ‘Treatment As Usual’ (TAU). Methods: Randomized controlled trial involving 2-year follow-up by personal interview and mortality register data through 27 years of 200 women first time treated for alcohol use disorder (AUD; EWA, n = 100 and TAU, n = 100), who were consecutively recruited during 1983–1984. Data from the Causes of Death Register were used to test for mortality differences related to group interaction predictors such as age, inpatient versus outpatient status at intake and 2-year drinking outcome. Results: Significantly lower mortality was found among younger women who participated in EWA compared with those who received TAU. This difference lasted nearly 20 years after intake to treatment. For women who only needed outpatient treatment, reduced mortality was found in the EWA group, even for older women. Increased mortality was found for TAU women who did not attend the 2-year follow-up compared with those who attended; no such difference was found for EWA women. This indicates different attrition mechanisms in the two groups. Thus, previously reported treatment effects may have been underestimated. EWA was a more comprehensive programme than TAU while also being single gender. Conclusions: EWA, specifically developed to meet a broad spectrum of problems among women with AUDs, was more effective than TAU, a mixed gender programme. It was not possible to separate whether this was in part because it was a more comprehensive programme, as well as being single gender.

Aims

For well over a decade, the Important People Inventory (IP, Clifford and Longabaugh, 1991; Clifford et al., 1992) has been used to collect a wide range of valuable information regarding network support for alcohol use. However, because of psychometric limitations and varied adaptations of the IP, the following study performed factor analyses to develop a more structurally consistent model of the scale as compared to the existing model.

Methods

A first principal components analysis (Varimax rotation) was run on the indices of the IP using data from a national investigation of residents within a recovery community (N = 897). Next, a second principal components analysis was run using data collected from participants recruited from inpatient treatment settings (N = 150).

Results

Results indicated a nine-index, three-factor model, which explained about two thirds of the common variance. These three factors included: Support for Drinking from Network Members (3 items), Drinking Behaviours of Network Members (3 items), and General Social Support (3 items).

Conclusions

Results of both studies suggest that the IP fits a multi-component structure. It is recommended that Drinking Behaviours of Network Members be examined for predictive validity and that General Social Support be removed from the scale or have additional items added.

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.