A Preliminary Study of Acute Responses to Clamped Alcohol Concentration and Family History of Alcoholism

BACKGROUND: The clamping method of alcohol administration was combined with a battery of dependent measures of frontal lobe brain function, and a novel index of acute adaptation, in a preliminary study in order to explore the paradigm's sensitivity to a familial history of alcoholism (FHA). METHODS: Ten family history-positive (FHP) and 10 family history-negative (FHN) adult social drinkers of both genders underwent alcohol clamping. Twenty minutes after the start of an intravenous infusion of alcohol, the breath alcohol concentration was clamped at a target of 60+/-5 mg/dl for 150 min. Initial and adaptive responses to alcohol were assessed using scalar indices of change. One index assessed initial improvements or impairments in brain function after alcohol. The other index assessed acute adaptation (tolerance or sensitization) to alcohol while the brain's exposure to alcohol was held constant. The battery of dependent measures included subjective perceptions, neuropsychological tests, saccadic eye-movement tasks, and event-related potential (ERP) tasks. Effect sizes for FHA were estimated for 10 dependent variables that showed adequate baseline test-retest reliability (r>0.6). RESULTS: FHP subjects showed less intense initial responses to alcohol in subjective perceptions, but greater changes in the latency of volitional saccades and ERP P3 components than did the FHN controls. FHP subjects generally showed greater acute tolerance to alcohol than did controls, who showed more instances of acute sensitization at this moderate breath alcohol concentration. Effect sizes for FHA exceeded 0.4 in more than half of the indices. CONCLUSIONS: The BrAC clamping paradigm assesses initial and adaptive responses of a battery of behavioral and electrophysiological measures of frontal lobe function to ethanol that appear both reliable and sensitive to FHA.     

Self-reported subjective perception of intoxication reflects family history of alcoholism when breath alcohol levels are constant

BACKGROUND: The premise of this study is that the increased familial risk for alcoholism is associated with genetic determinants of the response to alcohol, characterized by sensitivity and adaptation. Following a single administration, sensitivity is the initial response to alcohol, expressed as the change in dependent measures from baseline. Adaptation of dependent measures within a single exposure to alcohol can be expressed as acute tolerance (recovery of dependent measures toward baseline values) or sensitization (movement of dependent measure further away from baseline values). This study tested the hypothesis that family history-positive (FHP) subjects are more sensitive and more adaptive to alcohol compared with family history-negative (FHN) subjects. METHODS: The initial response and development of adaptation to alcohol were assessed by using self-reported subjective perceptions during a breath alcohol concentration (BrAC) clamp of 60 mg%. The Biphasic Alcohol Effects Scale, the Sensation Scale and a visual analog scale of intoxication were acquired at baseline, after the BrAC clamp was established, and after maintenance of the clamp for 105 min. RESULTS: FHP subjects were more sensitive to alcohol compared with FHNs, as evidenced by greater changes in feelings of intoxication when the BrAC clamp was initially achieved. While the clamp was maintained, the FHP subjects adapted to the effects of alcohol and their perceptions of intoxication became indistinguishable from those of the FHN subjects. The FHP subjects had developed acute tolerance to alcohol, whereas the FHN subjects did not. Other self-reported perceptions of alcohol's effects did not distinguish between the groups. CONCLUSIONS: A differential family history of alcoholism was reflected in self-reported subjective perceptions of intoxication when the brain's exposure to a specified concentration of alcohol was held constant (BrAC of 60 mg%). FHP subjects reported greater intoxication after alcohol and subsequently developed acute tolerance to alcohol compared with FHN subjects.     

Response of saccadic eye movements to alcohol in African American and non-Hispanic white college students

BACKGROUND: The primary goal of this study was to evaluate how race and sex interact with the effects of a moderate dose of alcohol on different ocular control subsystems in African American (AA) and non-Hispanic white American (WA) college students. METHODS: Horizontal visually guided (VG) saccades and antisaccades (AS) of 80 young adult, healthy, AA and WA college students were recorded with an infrared system. Subjects ingested 10 aliquots of ethanol at 3 min intervals, with the aggregate dose precalculated to yield a peak breath alcohol concentration (BrAC) of 80 mg%. Data from the measures performed at baseline and the ascending and descending limbs of the BrAC at approximately 65 mg% were compared across race and sex by multivariate analysis of variance. A no-alcohol control session, performed in 20 of the subjects, documented test-retest reliability of the VG and AS measurements. RESULTS: Both AA and WA groups demonstrated slowing of AS and VG saccades after alcohol administration, but there was no significant effect of 65 mg% alcohol on VG accuracy or AS errors. AS latency recovered toward baseline values, whereas the slowing of VG latency/velocity progressed, during alcohol exposure. There were significant differences between AA and WA groups in the time course of VG latency after alcohol but not in most other dependent measures. No significant effects for sex were observed in any of the saccade measures. The faster disappearance of alcohol in WA compared with AA was replicated, and some measures demonstrated a significant, albeit small, negative correlation between the alcohol disappearance rate and impairing effects of alcohol on saccades. CONCLUSIONS: Prolonged latencies and unchanged percentage of errors reflect a differential effect of alcohol on neural function in specific areas (parietal eye field, superior colliculus, and frontal eye areas). Race may interact with the effect of ethanol on saccadic eye movements in a college student population.     

Subjective perceptions associated with the ascending and descending slopes of breath alcohol exposure vary with recent drinking history

Background: The differentiator model predicts that individuals with a positive family history of alcoholism (FHA) or heavy alcohol consumers will feel more sensitive to the effects of alcohol on the ascending phase of the blood alcohol content while feeling less sedated on the descending phase. This study tested whether subjective perceptions are sensitive to the slope of breath alcohol concentration (BrAC) and whether that sensitivity is associated with an FHA and/or recent drinking history (RDH). Methods: Family‐history‐positive (FHP, n = 27) and family‐history‐negative (FHN, n = 27) young adult nondependent drinkers were infused intravenously with alcohol in 2 sessions separated by 1 week. After 20 minutes, one session had an ascending BrAC (+3.0 mg%/min), while the other session had a descending BrAC (?1 mg%/min). The BrAC for both sessions at this point was approximately 60 mg%, referred to as the crossover point. Subjective perceptions of intoxication, high, stimulated, and sedation were sampled frequently and then interpolated to the crossover point. Within‐subject differences between ascending and descending responses were examined for associations with FHA and/or RDH. Results: Recent moderate drinkers reported increased perceptions of feeling intoxicated (p < 0.023) and high (p < 0.023) on the ascending slope compared with the descending slope. In contrast, recent light drinkers felt more intoxicated and high on the descending slope. Conclusions: Subjective perceptions in young adult social drinkers depend on the slope of the BrAC when examined in association with RDH. These results support the differentiator model hypothesis concerning the ascending slope and suggest that moderate alcohol consumers could be at risk for increased alcohol consumption because they feel more intoxicated and high on the ascending slope. Subjects did not feel less sedated on the descending slope, contrary to the differentiator model but replicating several previous studies.     

Confirmation that offspring from families with alcohol-dependent individuals have greater hypothalamic-pituitary-adrenal axis activation induced by naloxone compared with offspring without a family history of alcohol dependence

BACKGROUND: This study was designed to confirm our previous findings that nonalcoholic offspring from families with alcohol-dependent individuals have greater hypothalamic-pituitary-adrenal axis activation induced by opioid blockade compared with nonalcoholic subjects without a family history of alcohol dependence. METHODS: Sixty-four nonalcoholic subjects aged 18 to 25 years were enrolled in the protocol. Twenty-seven subjects were offspring from families with alcohol dependence and were designated as family history-positive subjects (FHP). Thirty-seven subjects were biological offspring of non-alcohol-dependent parents and were designated as family history-negative subjects (FHN). Subjects received naloxone hydrochloride (0, 50, 125, 375, and 500 microg/kg) in double-blind, randomized order; adrenocorticotropin (ACTH) and cortisol were monitored over 120 min. RESULTS: No hormone differences at baseline or during placebo administration were identified between FHP and FHN subjects. FHP subjects had greater ACTH and cortisol response to opioid receptor blockade induced by naloxone hydrochloride compared with FHN subjects. CONCLUSIONS: These observations confirm previous findings that differences in ACTH and cortisol dynamics between FHP and FHN subjects can be unmasked by opioid receptor blockade.     

Thyrotropin and Prolactin Responses to Thyrotropin-Releasing Hormone in Young Men at High or Low Risk for Alcoholism

A reduced thyrotropin (TSH) response to TSH-releasing hormone (TRH) has been reported in a portion of abstinent alcoholic men without evidence of cirrhosis of the liver. It is not known whether this neuroendocrine change is a precursor of alcoholism or a sequelae of heavy alcohol consumption. Three of four published studies have found evidence for differences in TRH-induced TSH response in subjects at high risk for alcoholism, based on family history, compared with subjects at low risk for alcoholism. To test further the hypothesis that the TRH-induced TSH response is a vulnerability marker for alcoholism, we tested 25 young men with an alcoholic father [family history-positive (FHP)] and matched them, on alcohol consumption, to 25 young men with no identified first- or second-degree relatives with alcoholism [family history-negative (FHN)]. FHP subjects were further categorized based on whether their father had shown signs of alcohol problems before age 25 years (FHP-Early, n = 10) or after age 24 years (FHP-Late, n = 12). FHP subjects did not differ from FHN subjects in their baseline levels of thyroid hormones, glucose, Cortisol, or TSH. However, the distribution of TSH responses in the FHP subjects was skewed toward lower values, compared with FHN subjects ( p = 0.12). Furthermore, FHP-Late subjects had lower TSH responses than FHN subjects ( p = 0.02), whereas the TSH response of FHP-Early subjects was not different from FHN subjects. Prolactin responses to TRH were similar across all groups. These findings support the hypothesis that the TRH-induced TSH response may be a marker of vulnerability to alcoholism and suggest an association between the marker and risk for late-onset alcoholism.     

Effects of a moderate evening alcohol dose. I: sleepiness

Background: Few studies examining alcohol's effects consider prior sleep/wake history and circadian timing. We examined introspective and physiological sleepiness on nights with and without moderate alcohol consumption in well-rested young adults at a known circadian phase.
Methods: Twenty-nine adults (males=9), ages 21 to 25 years ( M =22.6, SD=1.2), spent 1 week on an at-home stabilized sleep schedule (8.5 or 9 hours), followed by 3 in-lab nights: adaptation, placebo, and alcohol. Alcohol (vodka; 0.54 g/kg for men; 0.49 g/kg for women) or placebo beverage was consumed over 30 minutes ending 1 hour before stabilized bedtime. In addition to baseline, 3 sleep latency tests (SLTs) occurred after alcohol/placebo ingestion (15, 16.5, and 18 hours after waking). Stanford Sleepiness Scales (SSS) and Visual Analog Scales (VAS) of sleepiness were completed before each SLT and approximately every 30 minutes. The Biphasic Alcohol Effects Scale (BAES) was administered a total of 4 times (baseline, 5, 60, and 90 minutes postalcohol/placebo). Subjects' circadian phase was determined from melatonin levels in saliva samples taken at approximately 30-minute intervals.
Results: All sleepiness and sedation measures increased with time awake. Only SSS and BAES sedation measures showed higher levels of sleepiness and sedation after alcohol compared with placebo. The mean circadian phase was the same for assessments at both conditions.
Conclusions: Alcohol did not increase physiological sleepiness compared with placebo nor was residual sedation evident under these conditions. We conclude that the effects on sleepiness of a moderate dose of alcohol are masked when sleep–wake homeostatic and circadian timing influences promote high levels of sleepiness.     

Intravenous Ethanol Infusions Can Mimic the Time Course of Breath Alcohol Concentrations Following Oral Alcohol Administration in Healthy Volunteers

Background: Our previous studies have used intravenous (IV) clamping methods to demonstrate that family history positive (FHP) subjects exhibit a greater initial response to alcohol than family history negative (FHN) subjects. These results differ from other studies of family history of alcoholism (FHA) influences, most of which have used an oral alcohol challenge, suggesting that the route of administration may influence both the response to alcohol and FHA‐related differences in response. To examine this possibility, one approach would be to directly compare responses following oral and IV alcohol administration in the same subjects. There is, however, a 3‐ to 4‐fold variance, between‐ and within‐subjects, in the breath alcohol concentrations (BrACs) following oral alcohol administration. Thus, our objective was to characterize the between‐subject variability in the time course of BrACs following oral alcohol administration in healthy volunteers and to develop an IV infusion method to mimic the BrAC‐time course attained following oral alcohol in the same subject. Methods: This was a 2‐session study in young adult, healthy, nondependent drinkers. In the first session, subjects ingested an oral dose of alcohol, based on total body water, to achieve a target peak BrAC of 80 mg%. In the second session, subjects received an IV infusion of ethanol designed to achieve the same BrAC time course as that achieved in the first session. The individualized infusion‐rate profile was precomputed using a physiologically‐based pharmacokinetic (PBPK) model for alcohol with model parameters adjusted to the individual’s physiology. The peak BrACs (C_max), times of peak BrAC (T_max), and the areas under the BrAC vs. time curve (AUC) were compared between sessions to assess how closely the BrAC exposure during the IV infusion session mimicked the exposure following oral alcohol. Results: The time course of BrACs following oral alcohol administration showed a high degree of between‐subject variability. Mean C_max, T_max, and AUC did not differ by gender, indicating that calculation of oral doses based on total body water results in comparable BrAC‐time courses, on average, for females and males. The IV infusion driven BrAC‐time profiles demonstrated good fidelity to the BrAC‐time curves resulting from oral alcohol: the mean %difference in C_max and AUC were both 11%, while the mean %difference for T_max was 27%. This degree of variability is less than half that seen across individuals following oral alcohol administration, which was substantial [coefficient of variation (%CV) ranging from 22 to 52%]. Conclusions: Despite the use of standardized doses and controlled experimental conditions, there was substantial between‐subject variability in the BrAC time course following oral administration of alcohol. The PBPK‐model‐based infusion method can mimic the BrACs attained with oral alcohol for individual subjects. This method provides a platform to evaluate effects attributable to the route of administration on the response to alcohol, as well as the influence of determinants such as family history of alcoholism on the alcohol response.     

Naltrexone Increases the Latency to Drink Alcohol in Social Drinkers

We investigated the effects of naltrexone (NTX) on alcohol drinking, urge to drink alcohol, and alcohol-induced sensations and mood states in social drinkers consuming alcohol ad libitum in a cocktail bar. Sixteen college-age men and women participated in a double-blind, placebo-controlled, within-subjects, cross-over study. Subjects were tested during each of three drug conditions: NTX, 50 mg/day, po; inactive placebo; and no drug. Each treatment condition lasted 8 to 11 days. Small groups of subjects consumed alcohol ad libitum during three 2-hr evening drinking sessions, separated by ˜2 weeks. NTX treatment significantly increased the latency (time in seconds) to first sip the first ( p < 0.05) and second alcoholic beverages consumed ( p < 0.01). Moreover, the mean blood alcohol concentration at the end of the session was significantly lower when subjects were treated with NTX ( p < 0.05). No differences were found on self-report urge to drink alcohol. Subjects reported more fatigue and tension on the Profile of Mood States ( p < 0.05), before drinking, and increases in nausea on the Alcohol Sensation Scale ( p < 0.05) when treated with NTX. The increase in the latency to sip the first and second alcoholic beverages may reflect the capacity of NTX to block urge for alcohol elicited from external cues (before consuming alcohol), as well as urge for alcohol after priming from ingested alcohol. Thus, the effectiveness of NTX for reducing drinking behaviors of alcoholics may be partially caused by anticraving properties of NTX.     

Sleep following alcohol intoxication in healthy, young adults: effects of sex and family history of alcoholism

Background: This study evaluated sex and family history of alcoholism as moderators of subjective ratings of sleepiness/sleep quality and polysomnography (PSG) following alcohol intoxication in healthy, young adults. Methods: Ninety‐three healthy adults [mean age 24.4 ± 2.7 years, 59 women, 29 subjects with a positive family history of alcoholism (FH+)] were recruited. After screening PSG, participants consumed alcohol (sex/weight adjusted dosing) to intoxication [peak breath alcohol concentration (BrAC) of 0.11 ± 0.01 g% for men and women] or matching placebo between 20:30 and 22:00 hours. Sleep was monitored using PSG between 23:00 and 07:00 hours. Participants completed the Stanford Sleepiness Scale and Karolinska Sleepiness Scale at bedtime and on awakening and a validated post‐sleep questionnaire. Results: Following alcohol, total sleep time, sleep efficiency, nighttime awakenings, and wake after sleep onset were more disrupted in women than men, with no differences by family history status. Alcohol reduced sleep onset latency, sleep efficiency, and rapid eye movement sleep while increasing wakefulness and slow wave sleep across the entire night compared with placebo. Alcohol also generally increased sleep consolidation in the first half of the night, but decreased it during the second half. Sleepiness ratings were higher following alcohol, particularly in women at bedtime. Morning sleep quality ratings were lower following alcohol than placebo. Conclusions: Alcohol intoxication increases subjective sleepiness and disrupts sleep objectively more in healthy women than in men, with no differences evident by family history of alcoholism status. Evaluating moderators of alcohol effects on sleep may provide insight into the role of sleep in problem drinking.     

Effects of aripiprazole on subjective and physiological responses to alcohol

Background:  Aripiprazole is an atypical antipsychotic with partial agonist activity at D₂ receptors, which could reduce the reinforcing effects of alcohol. The present study examined whether aripiprazole modifies the behavioral and physiological effects of a moderate dose of alcohol in a group of social drinkers.
Methods:  Eighteen healthy subjects (9 men; mean age = 27.6 years) completed a double-blind, within-subject study with 3 experimental sessions in a randomized sequence, during which they received no medication, aripiprazole 2.5 mg, or aripiprazole 10 mg on the day prior to the laboratory session. During the session, subjects consumed alcohol that was served as three standardized drinks (i.e., a total of 0.8 g/kg for men and 0.7 g/kg for women). Breath alcohol concentration (BrAC), heart rate, blood pressure, static ataxia, and subjective effects were measured regularly throughout the laboratory sessions.
Results:  Alcohol consumption produced physiological and subjective responses that were consistent with the literature on its effects. Pre-treatment with aripiprazole was generally well tolerated, with tiredness being the most commonly reported adverse event. The medication was associated with modest physiological effects. It also significantly and dose-dependently increased the sedative effects of alcohol and, to a lesser degree, decreased the euphoric effects of alcohol.
Conclusions:  These findings require replication in a larger subject sample that includes heavy drinkers and in a study that employs a placebo session. Based on its capacity to increase the sedative effects and decrease the euphoric effects of alcohol, aripiprazole could be of value in the treatment of heavy drinking.     

The effect of tryptophan depletion on alcohol self-administration in non-treatment-seeking alcoholic individuals

BACKGROUND: Alcohol self-administration in the laboratory has been used to evaluate pharmacological treatments and neurobiological mechanisms that underlie alcohol use in alcohol-dependent individuals. This study evaluated whether attenuation of serotonin synthesis via depletion of its precursor tryptophan reduces the amount of alcohol consumed in a self-administration paradigm in non-treatment-seeking individuals with alcohol use disorders. METHODS: Individuals with alcohol dependence (n = 8) and alcohol abuse (n = 4) who were not seeking treatment were recruited by advertisement and participated in two test days, 1 week apart. Each test session was preceded by administration of a concentrated amino acid drink that resulted in a rapid and significant decline in plasma free tryptophan (active depletion) or a similar drink containing tryptophan (placebo depletion). Tests were conducted in a randomized, double-blind fashion. The test session began with a cue exposure session where subjects were exposed to their favorite alcoholic beverage and asked to rate their craving for alcohol. After this, subjects were administered a priming drink designed to raise blood alcohol levels to 0.02 g%. Subjects then had the opportunity to drink up to eight additional drinks, each designed to raise blood alcohol levels by 0.02 g%, or to receive $3 for each drink not consumed over a 2-hr period. RESULTS: There were no significant differences in alcohol consumed or subjective intoxication with active tryptophan depletion compared with placebo. Self-reported craving correlated with the amount of alcohol consumed in the session. CONCLUSIONS: These data question the dependence of alcohol self-administration on the ongoing synthesis of serotonin.     

Vagal Mediation of the Effect of Alcohol on Heart Rate

Alcohol (0.5 g/kg bodyweight) was administered in two sessions and placebo in a third session to normal, healthy social drinkers. A control group was administered a mixer (i.e., no alcohol) for each of the three sessions. The heart rate and vagal tone index (V) response patterns were different to alcohol than to the mixer or placebo. The treatments did not differentially influence pulse transit time. The results indicated that the acute effect of a moderate dose of alcohol on the heart is parasympathetically (i.e., vagally) mediated and has no significant direct sympathetic component.     

A 6-month controlled naltrexone study: combined effect with cognitive behavioral therapy in outpatient treatment of alcohol dependence

BACKGROUND: In several studies, patients with alcohol dependence treated with the opioid antagonist naltrexone have shown fewer relapses to heavy drinking than those receiving placebo. An interaction between the naltrexone effect and the type of psychological therapy has been observed. METHODS: A 6-month, double-blind, placebo-controlled, parallel-group study was performed at 10 different investigation sites. After a placebo run-in period of 1 week, 118 patients were randomized into 4 treatment groups-50 mg of naltrexone daily or placebo in combination with either cognitive behavioral therapy (CBT) or supportive therapy. The CBT was performed over nine sessions according to the manual of Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity). The supportive therapy was defined as "the treatment as usual." Alcohol consumption, craving, carbohydrate-deficient transferrin, medication compliance by tablet count, and adverse clinical events were assessed at all visits. Other liver enzymes and psychiatric symptoms were also determined. RESULTS: Ninety-one (77%) patients completed the study, and 92 (78%) were 80% compliant with the medication regimen. A lower percentage of heavy-drinking days was shown in the naltrexone group (p = 0.045) compared with the placebo group, as was a lower craving score (p = 0.029). These results are supported by the lower levels of liver enzyme activities (p < 0.010 for aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase), but not by the carbohydrate-deficient transferrin levels, in the naltrexone group. The mean time period before the first day of heavy drinking was longer for the group treated with CBT (p = 0.010), especially in combination with naltrexone (p = 0.007). Naltrexone was well tolerated, and no patients discontinued the study due to side effects. CONCLUSIONS: This study supports the effect of naltrexone in outpatient treatment of alcohol dependence and suggests that a beneficial interaction effect with CBT can be expected.     

Effect of Citalopram on Alcohol Intake in Heavy Drinkers

The effect of the selective serotonin reuptake inhibitor citalopram (40 mg daily dose) on alcohol intake was investigated in a doubleblind, placebo-controlled cross-over study. Thirty men with heavy alcohol consumption (mean daily alcohol intake 111 ± 51 g pure alcohol) completed the study. After a 2-week baseline period, subjects were randomly allocated to treatment with either citalopram or placebo for 5 weeks. In the total sample of heavy drinkers, no difference was found between citalopram and placebo treatment in alcohol consumption or days of abstinence. However, the response to citalopram was negatively correlated ( r _a=–0.67, p < 0.01) with baseline levels of mean daily alcohol intake. Therefore, we divided the total sample into two subgroups with baseline mean daily alcohol intake above and below median (107 g pure alcohol), respectively. In the group with the higher baseline values (138 ± 25 g pure alcohol), citalopram was not different from placebo in reducing the daily alcohol intake, but in subjects with the lower baseline values (85 ± 15 g pure alcohol), citalopram was significantly ( p < 0.01) superior to placebo. Consequently, citalopram at the present dose appears capable of reducing alcohol intake only in a subgroup of heavy drinkers with a mean daily consumption of between 60 and 100 g pure alcohol.     

Examining naltrexone and alcohol effects in a minority population: results from an initial human laboratory study

Prior clinical findings have indicated a potential lack of naltrexone efficacy among African Americans with alcohol dependence. However, no definitive conclusions have been drawn due to the relatively small numbers of African Americans in most alcohol treatment trials. The purpose of this study was to examine alcohol and naltrexone effects on healthy African-American individuals in a laboratory environment. Nonalcohol-dependent social drinking adults of African descent (n = 43) were recruited for participation. After consenting and completing the baseline assessment, they participated in four separate alcohol challenge sessions each separated by at least 10 days. During each of the sessions, subjects were administered alcohol or sham drinks, after pretreatment with either naltrexone (50 mg/day) or placebo in a double-blind fashion. The order of the four sessions was randomly assigned. During each session, breath alcohol levels and subjective responses were measured. Results indicate an alcohol effect among these subjects for subjective responses, but no naltrexone effect. Similar to the apparent lack of clinical efficacy findings, naltrexone does not appear to impact alcohol effects in African-American social drinkers. Future studies should investigate African-American populations with heavy drinking as well as alcohol-dependent subjects in order to strengthen the parallels to clinical findings.     

Ritanserin, a central 5-HT2 antagonist, in heavy social drinkers: desire to drink, alcohol intake and related effects

Ritanserin, a 5-HT₂ receptor antagonist, decreased alcohol intake in some, but not all, animal studies and in an open clinical study. We tested the short-term effects of ritanserin in 39 (35 male, four female) heavy social drinkers (consuming at least 28 drinks/week), aged 19–63 years, who were not seeking treatment. After an intake assessment, they received placebo for 7 days in a single-blind baseline. They were then randomly assigned to one of three double-blind treatments for 14 days: ritanserin 5 tag/day (n= 12), ritanserin 10 mg/day (n= 13) or placebo (n= 14). Subjects recorded daily outpatient alcohol intake. Feelings of intoxication and interest, desire, craving and liking for alcohol were rated retrospectively at each weekly study visit. Experimental drinking sessions were conducted after baseline (EDS₁) and treatment (EDS₂); in each session subjects were offered 18 mini-drinks (total = six standard) and rated their desire to drink, intoxication and mood (POMS). Outpatient results: ritanserin 5 mg/day decreased desire and craving for alcohol (vs. baseline, p < 0.05) but not alcohol intake. Liking of alcohol decreased from baseline with ritanserin 10 mg/day (p = 0.01) and placebo (p = 0.05). Changes in alcohol intake from baseline with ritanserin 10 mg/day (increase, p > 0.05) and placebo (decrease, p > 0.05) were different (p < 0.05). EDS results: in EDS₂, desire ratings for the first three mini-drinks were lower after ritanserin 5 mg/day than after ritanserin 10 mg/day (p < 0.05), but the decreases were not statistically significant when EDS₁ desire ratings were controlled for. Ritanserin 10 mg/day increased alcohol-induced feelings of intoxication and friendliness, compared with placebo (p < 0.05). Both ritanserin 5 mg/day and 10 nig/day enhanced alcohol-induced decreases in fatigue, compared with placebo (p < 0.05). These results indicate that ritanserin may have differential effects on alcohol intake, desire, craving and liking, intoxication and some of alcohol's effects on mood. However, they suggest that ritanserin has limited efficacy in reducing alcohol intake in heavy drinkers.     

Apomorphine-induced growth hormone response is attenuated by ethanol but not dextromethorphan

BACKGROUND: Misuse of alcohol drinking is a major health problem. Alcohol decreases spontaneous growth hormone (GH) secretion, but the mechanism is unclear. The aim of this study was to test whether administration of alcohol (study 1) or a N-methyl d-aspartate (NMDA) receptor antagonist (study 2) attenuates the GH response to pharmacological dopaminergic stimulation. METHODS: The 2-session repeated measures design was conducted at the endocrine laboratory at the Department of Psychiatry at the Free University Berlin. Twenty healthy Caucasian males aged 35+/-10 years without a history of alcohol use disorders were tested using the Apomorphine (APO) challenge test. In study 1, we injected APO (0.01 mg/kg s.c.) 1 hour after oral administration of 1 g/kg ethanol and placebo, respectively. In study 2, the APO challenge was conducted after 0.3 mg/kg dextromethorphan (DXM) and placebo. The main outcome measures were the peak serum GH concentration and area under the time/concentration curve up to 120 minutes after APO. The effects of ethanol and DXM were tested using the Wilcoxon signed-rank tests. RESULTS: Compared with placebo, alcohol significantly decreased the APO-induced GH release (mean and SEM peak GH concentration 19.9+/-3.2 vs 6.2+/-1.9 ng/mL, p=0.002). Dextromethorphan did not change APO-induced GH response (22.5+/-5.4 vs 21.0+/-5.8 ng/mL, p=0.105). CONCLUSION: A single intermediate alcohol dose markedly reduces GH response to dopaminergic stimulation. Although alcohol is thought to stimulate dopaminergic function in certain pathways, but not necessarily in the hypothalamus, our results are in line with the alcohol effect on baseline GH secretion. Growth hormone suppression appears not to be mediated by ethanol's NMDA-antagonistic properties.     

Videotaped cue for urge to drink alcohol

BACKGROUND: The urge to drink alcohol can be robustly and reliably induced via actual exposure to a person's preferred alcoholic beverage. Unfortunately, these exposure paradigms are unwieldy for functional magnetic resonance imaging studies. The goal of this study was to examine whether viewing a personalized videotaped cue could induce alcohol craving. The following hypotheses were tested: (1) individualized cue videotapes can reliably elicit the urge to drink alcohol in alcohol-dependent participants and (2) alcohol drinking histories can predict reactivity to cue. METHODS: DSM-IV criteria were used to identify an alcohol-dependent group (ADG). Controls included a light-drinking group and a moderate-drinking group. Urge to drink alcohol was assessed at baseline and after each of five in vivo exposure conditions: water (W), alcohol 1 (A1), mood induction (M), alcohol 2 (A2), and relaxation (R). The entire exposure session was videotaped. Each participant's video footage was digitally edited to produce a 17.5-min cue that was presented to the participant 24 to 72 hr later. Ratings of urge to drink alcohol across the five exposure conditions were compared for both the in vivo and the video exposure sessions. RESULTS: Fourteen participants (five in the light-drinking group, four in the moderate-drinking group, and five in the ADG) completed both sessions. Participants in each group showed differences between neutral cue exposure (W and R) and alcohol-related cue exposure (A1, M, and A2) in both the in vivo cue session (p < 0.002) and the videotape session (p < 0.02). Post hoc comparisons among the groups to alcohol-related cues established that, in both sessions (p(in vivo) = 0.04; p(videotape) = 0.04), the ADG demonstrated the greatest urge to drink. CONCLUSIONS: Alcohol cue reactivity can be reliably induced and assessed in alcohol-dependent participants via personalized videotapes. History of alcohol consumption is positively correlated with the degree of cue reactivity. This study advances our ability to assess alcohol cue reactivity in the absence of alcohol.     

Deficits in eye movement control in children with fetal alcohol spectrum disorders

BACKGROUND: Prenatal exposure to alcohol can result in a spectrum of adverse developmental outcomes in offspring, collectively termed fetal alcohol spectrum disorders (FASD). Deficits in executive function--the psychological processes involved in controlling voluntary goal-oriented behavior--are prevalent in FASD. Oculomotor tasks have been designed as highly sensitive tools to evaluate components of executive function. Because of the extensive overlap in the brain areas controlling eye movements and those affected in FASD, we hypothesized that individuals with FASD display specific neurobehavioral abnormalities that can be quantified with eye movement testing. METHODS: Subjects (8-12 years old) were instructed to look either toward (prosaccade) or away from (antisaccade) a stimulus that appeared in the peripheral visual field. Two fixation conditions were used. In the gap condition, the central fixation point (FP) was removed before the appearance of the peripheral stimulus; in the overlap condition, the FP remained illuminated. Saccadic reaction times (SRTs, time from stimulus appearance to saccade initiation), direction errors (saccades made in the incorrect direction relative to instruction), and express saccades (short-latency: SRT=90-140 ms) were measured to assess automatic and volitional saccade control. RESULTS: Compared with controls, FASD children had elongated reaction times, excessive direction errors, and no express saccades. Metric analysis of correct prosaccades revealed a trend toward increased saccadic duration and decreased saccadic velocity in FASD subjects. CONCLUSION: These results reflect deficits in executive function and motor control, and are consistent with dysfunction of the frontal lobes, possibly due to disrupted inhibitory mechanisms. Therefore, eye movement tasks may be powerful and easy tools for assessing executive function deficits in FASD.