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Role of GABA(B) receptor in alcohol dependence: reducing effect of baclofen on alcohol intake and alcohol motivational properties in rats and amelioration of alcohol withdrawal syndrome and alcohol craving in human alcoholics.

The present paper describes the results of recent preclinical and clinical studies conducted in this laboratory in order to characterize the anti-alcohol properties of the GABA(B) receptor agonist, baclofen. At a preclinical level, the repeated administration of non-sedative doses of baclofen dose-dependently suppressed the acquisition and maintenance of alcohol drinking behavior in selectively bred Sardinian alcohol-preferring (sP) rats tested under the homecage, 2-bottle "alcohol vs water" choice regimen. Acute injection of baclofen completely blocked the temporary increase in voluntary alcohol intake occurring after a period of alcohol abstinence (the so-called alcohol deprivation effect, which models alcohol relapses in human alcoholics). Acute treatment with baclofen also dose-dependently suppressed extinction responding for alcohol (an index of motivation to consume alcohol) in sP rats trained to lever-press for oral alcohol self-administration. Taken together, these results suggest the involvement of the GABA(B) receptor in the neural substrate mediating alcohol intake and alcohol motivational properties in an animal model of excessive alcohol consumption. Further, acutely administered baclofen dose-dependently reduced the severity of alcohol withdrawal signs in Wistar rats made physically dependent upon alcohol. Preliminary clinical surveys suggest that the anti-alcohol properties of baclofen observed in rats may generalize to human alcoholics. Indeed, a double-blind survey demonstrated that repeated daily treatment with baclofen was associated, when compared to placebo, with a higher percentage of subjects totally abstinent from alcohol and a higher number of days of total abstinence. Treatment with baclofen also suppressed the number of daily drinks and decreased the obsessive and compulsive components of alcohol craving. Finally, a single non-sedative dose of baclofen resulted in the rapid disappearance of alcohol withdrawal symptomatology, including delirium tremens, in alcohol-dependent patients. In both clinical studies, baclofen was well tolerated with minimal side effects. These results suggest that baclofen may represent a potentially effective medication in the treatment of alcohol-dependent patients.

Alcohol Drinking↗

Polymorphism of alcohol dehydrogenase, alcohol and aldehyde dehydrogenase activities: implication in alcoholic cirrhosis in white patients. The French Group for Research on Alcohol and Liver.

Two types of factors can theoretically modulate alcohol metabolism toward increased acetaldehyde production. These factors are the following: (a) individual, genetically determined isoenzymes with distinct catalytic properties, and (b) modifications of enzyme activity induced by alcohol itself or liver damage. To investigate the respective roles of these factors in white individuals, we studied the alcohol dehydrogenase phenotype, together with liver alcohol dehydrogenase and aldehyde dehydrogenase activities, in 161 patients. Patients with alcoholic cirrhosis (n = 31) were compared with three types of controls: patients with nonalcoholic cirrhosis (n = 25) and excessive (n = 62) and moderate drinkers (n = 43) without liver disease. No association between alcohol dehydrogenase-3 phenotype and alcoholic cirrhosis was found. The prevalence of atypical alcohol dehydrogenase in the four groups was less than 1%. Patients with cirrhosis, regardless of its cause, had significantly lower alcohol dehydrogenase activity than the patients without cirrhosis (p less than 0.05 and p less than 0.01 vs. excessive and moderate drinkers, respectively). Among the noncirrhotic patients, alcohol dehydrogenase activity was significantly lower in the excessive drinkers than in the moderate drinkers (p less than 0.001). Aldehyde dehydrogenase activity was not different between cirrhosis-free excessive and moderate drinkers; in contrast, compared with these two groups, it was significantly lower in the two cirrhosis groups (p less than 0.01). These results suggest that no phenotypic pattern of alcohol dehydrogenase-3 associated with alcoholic cirrhosis in white patients exists, that liver alcohol dehydrogenase activity falls as a consequence of both alcohol abuse and cirrhosis and that liver aldehyde dehydrogenase activity is unaffected by alcohol abuse and only falls after the onset of cirrhosis.

Adult↗

Lower packing density of glial fibrillary acidic protein-immunoreactive astrocytes in the prelimbic cortex of alcohol-naive and alcohol-drinking alcohol-preferring rats as compared with alcohol-nonpreferring and Wistar rats.

BACKGROUND: Low packing density of glial cells, possibly astrocytes, has been described in the prefrontal cortex and hippocampus of "uncomplicated" alcoholics. Astrocytes perform crucial support functions in the processing of neurotransmitters and transfer of energy substrates from blood to cortical neurons. It is still unknown whether attrition in the numbers of astrocytes is only a consequence of prolonged alcohol abuse or also predates the exposure to alcohol in subjects at risk for alcohol dependence. METHODS: We used alcohol-preferring (P) rats exposed ad libitum for 2 or 6 months to either water only or 10% ethanol and alcohol-nonpreferring (NP) rats and nonselected Wistar rats exposed only to water for 2 months. Sections through the rat frontal cortex were immunostained for glial fibrillary acidic protein (GFAP), a specific marker of astrocytes. The packing density of GFAP-immunoreactive (IR) astrocytes and the area fraction of GFAP immunoreactivity were measured in the prelimbic cortex (PLC) using the dissector probe and analysis of binary images of GFAP immunostaining, respectively. RESULTS: The packing density of GFAP-IR astrocytes was significantly lower in both alcohol-naive and alcohol-exposed P rats than in NP rats or Wistar rats. The area fraction of GFAP immunoreactivity was significantly lower in the alcohol-exposed P rats than in NP rats, Wistar rats, and alcohol-naive P rats. CONCLUSION: These results suggest that low density of GFAP-IR astrocytes in the PLC of P rats predates the exposure to alcohol and might be a factor contributing to the increased risk for alcohol dependence. In addition, prolonged free-choice alcohol drinking may reduce the extent of GFAP-IR processes in the PLC of P rats.

Alcohol Drinking↗

Changes in blood alcohol levels as a function of alcohol concentration and repeated alcohol exposure in adult female rats: potential risk factors for alcohol-induced fetal brain injury.

Fetal alcohol syndrome and alcohol-related birth defects are the result of heavy maternal alcohol consumption during gestation. The magnitude of deficit manifested by the offspring is invariably a consequence of several risk factors that may result in high peak blood alcohol concentrations (BACs), such as the duration, timing, or pattern of alcohol consumption. In addition, the alcohol content of the consumed beverage may play a role in determining offspring developmental consequences. Because higher BACs are positively correlated with risk and severity of brain injury early in postnatal life, initially it was important to determine how BAC is influenced by alcohol concentration and whether that influence is constant over repeated alcohol treatments. Groups of female Sprague-Dawley rats received daily intragastric intubations of 5 g/kg alcohol in one of several concentrations: 45% (v/v), 30% (v/v), 22.5% (v/v), or 15% (v/v) for a duration of 18 consecutive days. Blood samples were taken at various times postintubation on days 3, 8, 13, and 18 of treatment, and analyzed by headspace gas chromatography. Multivariate analyses of peak BAC, average BAC, and time to reach peak BAC revealed some noteworthy results. First, peak BAC and average BAC were significantly lower in the 45% group, compared with the other concentration groups, whereas this group also took a longer time to reach peak BAC than the other three groups. Second, peak BAC and average BAC were higher on the last day of treatment than any of the other treatment days. These results suggest that alcohol concentration and repeated alcohol exposure can influence BAC and, as such, are important risk factors to be considered in the appraisal of alcohol-induced fetal brain injuries.

Animals↗

Differences and similarities in development of drinking behavior between alcoholic offspring of alcoholics and alcoholic offspring of non-alcoholics.

Self-reported initial, early, and long-term drinking behaviors, experiences, and consequences were obtained from male alcoholics completing inpatient treatment. Subjects were recruited and selected on the basis that they met DSM-III criteria for diagnosis of alcohol dependency and that their biological fathers were alcoholic (FHP; Family History Positive) or that they had no biological family history of alcoholism (FHN; Family History Negative). Results indicated that FHP subjects rated their initial taste of beer higher than FHN subjects, that FHP subjects began tasting and subsequently regularly drinking alcohol at an earlier age than FHN subjects and that there was significantly shorter elapsed time between initiating regular drinking and developing alcoholic-symptomatic problems in living among FHP alcoholics than FHN alcoholics. Although there were a few other significant differences, the drinking-behavioral histories of the two groups were remarkably similar and parallel. Taken together, results suggest that familial risk factors primarily influence the rate at which alcoholic drinking and alcoholism develop, rather than the form or pattern of alcoholic drinking.

Adult↗

Validity of carbohydrate-deficient transferrin (%CDT), gamma-glutamyltransferase (gamma-GT) and mean corpuscular erythrocyte volume (MCV) as biomarkers for chronic alcohol abuse: a study in patients with alcohol dependence and liver disorders of non-alcoholic and alcoholic origin.

AIM: To test the clinical performance of carbohydrate-deficient transferrin (%CDT), gamma-glutamyltransferase (gamma-GT) and mean corpuscular erythrocyte volume (MCV) as biomarkers for alcoholism with a special focus on patients suffering from liver diseases. DESIGN: Well-characterized collectives of alcohol-dependent patients with current consumption (ALC patients, n = 101), and relevant control groups (115 social drinkers, 46 patients with unspecifically increased gamma-GT, 51 hepatitis patients and 20/31 patients with non-alcohol/alcohol-dependent liver cirrhosis) were included into the study. The Positive Alcohol Use Disorders Test (AUDIT) score, International Classification of Diseases version 10 (ICD-10)/Diagnostic and Statistical Manual version IV (DSM-IV) criteria and blood drawn within 4 days of last drinking were inclusion criteria for subjects with regular heavy drinking. %CDT was determined using an automated assay which recently had been completely modified. FINDINGS: Median AUDIT scores of patients without/with regular heavy drinking were 1-3/27. The following medians/95th percentiles were obtained for %CDT: social drinkers 2.2/3.0, patients with unspecifically increased gamma-GT 2.1/3.0, hepatitis 2.0/4.4, non-alcohol-dependent liver cirrhosis 2.4/4.8, alcohol-dependent liver cirrhosis 3.0/5.9, ALC patients 3.9/14.9. Differences between patients without and with alcohol abuse were highly significant (P < 0.001). No differences in CDT values were found between males and females. There was no correlation between %CDT values, gamma-GT, MCV and the amount of alcohol consumed in ALC patients; 3.0%CDT (95th percentile social drinkers) is proposed as cut-off for the test used (Tina-quant %CDT 2nd-generation). At this cut-off, the sensitivity for ALC patients was 73.3%, whereas gamma-GT/MCV had a sensitivity of 71.3%/64.4%. Multivariate analysis performed at 95% specificity resulted in an improvement of the sensitivity by combining %CDT with gamma-GT (83.2%). A further enhancement of the sensitivity to 88.1% was obtained by combination of %CDT, gamma-GT and MCV. The diagnostic specificity of %CDT calculated at the cut-off of 3% was 93.5% in patients with unspecifically increased gamma-GT, 88.2% in hepatitis patients and 70.0% in patients with non-alcohol-dependent liver cirrhosis. %CDT was more specific in these patient collectives than MCV, and especially more than gamma-GT (specificity in hepatitis 52.9%, and 35.0% in non-alcohol-dependent liver cirrhosis). CONCLUSION: %CDT is of high diagnostic value to support diagnosis of alcohol-use disorders. The specificity of this marker in patient groups with liver disorders is superior to the biomarkers gamma-GT and MCV.

Adolescent↗

The impact of a family history of alcoholism on the relationship between age at onset of alcohol use and DSM-IV alcohol dependence: results from the National Longitudinal Alcohol Epidemiologic Survey.

Both the age at onset of alcohol use and a family history of alcoholism can influence a person's risk of becoming alcohol dependent. The relationship between lifetime alcohol dependence, age at first alcohol use, and a family history of alcoholism was investigated using data obtained in the 1992 National Longitudinal Alcohol Epidemiologic Survey. This analysis demonstrated that regardless of the family history of alcoholism, respondents with an earlier age of drinking onset were more likely to become alcohol dependent compared with respondents with a later age of drinking onset. Among all age, race, and gender subgroups studied, however, people with a family history of alcoholism had a higher prevalence of lifetime alcohol dependence than did people without such a history.

Age of Onset↗

The role of alcohol dehydrogenase and aldehyde dehydrogenase isozymes in alcohol metabolism, alcohol sensitivity, and alcoholism.

Isozymes of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) were studied in human organs and tissues using sensitive analytical techniques. Both ADH and ALDH showed an extensive polymorphism among different racial groups. In liver extracts and other tissues of Japanese an isozyme of ALDH (ALDH I) with a low Km for acetaldehyde was found to be deficient. The ALDH isozyme deficiency might account for the marked initial sensitivity to alcohol in Orientals owing to their impaired acetaldehyde oxidizing capacity. Significantly low erythrocyte ALDH activity was noted more frequently in chronic alcoholics than in healthy controls. After subcellular fractionation of livers from alcoholics a preferential damage of mitochondrial ALDH isozyme was observed. The metabolism of acetaldehyde has received considerable attention in the past few years, owing to the toxic effects of this substance. Rapid progress has been made in the understanding of the multiple molecular forms of ADH and ALDH in human tissues. Our recent studies have demonstrated that the isozymes of ALDH may play an important role in the pathogenesis of alcohol-related organ damage and in the biological sensitivity to alcohol in certain ethnic groups. A possible protection of ALDH I deficiency against alcoholism in Japanese has been discussed. More recent reports [Imprain et al, 1982; Jones, 1982] indicate that, in addition to the enzymatically active ALDH II, tissues from Orientals deficient in ALDH I isozyme contain enzymatically inactive, immunologically cross-reactive material homologous with ALDH I. Thus, the absence of ALDH I isozyme is not due to a regulatory mutation, a gene deletion, or a nonsense mutation, but probably results from a structural mutation.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Dehydrogenase↗

National Task Force on Fetal Alcohol Syndrome and Fetal Alcohol Effect: defining the national agenda for fetal alcohol syndrome and other prenatal alcohol-related effects.

Prenatal alcohol exposure can lead to serious birth defects and developmental disabilities. A need exists to develop effective strategies for both children with fetal alcohol syndrome (FAS) or other prenatal alcohol-related effects and for women at high risk for having an alcohol-exposed pregnancy. Since the syndrome was identified approximately 30 years ago, advancements have been made in FAS diagnostics, surveillance, prevention, and intervention, but a substantial amount of work remains. Collaborations among partners in federal state, and local agencies, academia, clinical professions, school systems, and families are critical to developing and implementing successful efforts related to FAS and fetal alcohol effect (FAE). In 1999, Congress directed the Secretary of the U.S. Department of Health and Human Services to convene the National Task Force on FAS and FAE (the Task Force). CDC's National Center on Birth Defects and Developmental Disabilities, Fetal Alcohol Syndrome Prevention Team, coordinates the Task Force and manages its operation. Since the Task Force was chartered in 2000, Task Force members, with input from multiple partners, have convened to deliberate and determine the Task Force mission, goals, and priority concerns to be addressed. This report describes the structure, function, mission, and goals of the Task Force and provides their first recommendations. An explanation of how the Task Force recommendations were generated and the Task Forces next steps are also reported.

Alcoholism↗

A descriptive study of alcohol-dependent women attending Alcoholics Anonymous, a regional council on alcoholism and an alcohol treatment unit.

A total of 86 women, attending three different agencies, were interviewed on their help-seeking behaviours for problem drinking. Each agency represented a different type of help available in the community. Self-help was represented by Alcoholics Anonymous; the non-statutory sector by a regional council on alcoholism's offices; and the statutory sector by an alcohol treatment unit's out-patient department. Differences between the groups in terms of demography and drinking history are explored in this paper. It was found that the regional council group resembled the female problem drinkers in other alcohol treatment agencies in terms of alcohol dependency, pattern of alcohol consumption and drinking styles, but differed in age and abstinence behaviour.

Adolescent↗

Effects of various serotonergic agents on alcohol intake and alcohol preference in Wistar rats selected at two different levels of alcohol preference.

Wistar rats can develop a high preference for 3% alcohol after a period of forced alcohol exposure and 2 days of alcohol withdrawal. If these rats are selected at a medium (> or = 60%) and a high (> or = 85%) level of alcohol preference, it is possible to study the effects of various compounds on alcohol intake and alcohol preference in rats with two different levels of alcohol preference. With this procedure, it was demonstrated that the benzodiazepine chlordiazepoxide can reduce alcohol preference at doses > or = 10.0 mg/kg in the high alcohol preference group, by increasing the water consumption without affecting alcohol drinking. Chlordiazepoxide had no effects in the medium alcohol preference group. The 5-HT uptake inhibitors fluoxetine and citalopram reduced alcohol intake and alcohol preference in both the medium and the high alcohol preference groups by means of a reduction in consummatory behaviour. Both drugs clearly affected total fluid intake and body weight gain. The 5-HT1A agent buspirone reduced alcohol intake and alcohol preference in the group of medium alcohol preferring rats at doses between 0.0025 and 0.63 mg/kg. The drug did not change water drinking so that total fluid consumption diminished. At doses > or = 2.5 mg/kg buspirone, there was an increased alcohol consumption. Buspirone was without important effects on the high alcohol preferring rats. The 5-HT3 antagonist ondansetron reduced alcohol intake in both the medium and high alcohol preferring rats at doses between 0.01 and 0.16 mg/kg. The drug had no effects on alcohol preference and water consumption. At some doses, there was a reduction in total fluid intake. The 5-HT2/1C antagonist ritanserin reduced alcohol intake and alcohol preference at doses between 0.04 and 2.50, and 0.16 and 10.0 mg/kg in the medium and high alcohol preferring rats, respectively. Together with the decrease in alcohol consumption there was an increase in water drinking, leaving total fluid intake unaffected. The activity of ritanserin was less pronounced in the high as compared to the medium alcohol preference group. These results indicate that various serotonergic agents can affect alcohol intake and alcohol preference by different mechanisms of action.

Alcohol Drinking↗

Effects of chronic alcohol treatment on acoustic startle reactivity during withdrawal and subsequent alcohol intake in high and low alcohol drinking rats.

AIMS: The purpose of the present study is to determine whether the inverse genetic association between alcohol withdrawal magnitude and genetic propensity for alcohol drinking that we have previously identified in alcohol-naive rats given alcohol acutely, would also be seen following chronic alcohol exposure. The effect of forced, chronic alcohol treatment on subsequent voluntary alcohol drinking was also examined. METHODS: Male rats from the high alcohol drinking (HAD2) and low alcohol drinking (LAD2) lines received two intragastric (IG) infusions of alcohol (3.0 g/kg BW; 25% v/v) or an equal volume of water, separated by 5 h, every day for 20 consecutive days (chronic alcohol treatment). Acoustic startle reactivity was assessed at 10, 14, and 18 h after the second infusion on days 1, 5, 10, 15, and 20. After acoustic startle testing was completed, all rats received two IG infusions of 3.0 g alcohol/kg BW, separated by 5 h, and blood alcohol content was assessed at 10, 14, and 18 h after the second alcohol infusion. All rats were then given a 24 h free-choice between alcohol and water for 8 weeks. RESULTS: Startle magnitude to a 120 dB tone was suppressed during alcohol withdrawal in both alcohol-treated HAD2 and LAD2 rats after 5, 10, and 15 days of alcohol treatment. Forced, chronic alcohol treatment produced metabolic tolerance in both the HAD2 and LAD2 lines and significantly suppressed subsequent voluntary alcohol intake in rats of the HAD2 line. CONCLUSIONS: Reduced acoustic startle reactivity during alcohol withdrawal in both HAD2 and LAD2 rats is consistent with our previous findings in the HAD2 but not the LAD2 line and may reflect reduced CNS excitability during withdrawal from forced alcohol exposure. Forced alcohol exposure robustly retarded the expression of a genetic predisposition toward alcohol drinking in rats selectively bred for high alcohol intake.

Acoustic Stimulation↗

Fetal alcohol exposure and temporal vulnerability regional differences in alcohol-induced microencephaly as a function of the timing of binge-like alcohol exposure during rat brain development.

In humans, microcephaly (small head for body size) is a common feature of fetal alcohol syndrome. An analogous measure, termed microencephaly (small brain for body size), can be used for evaluating the detrimental effects of the differential timing of alcohol exposure on brain development in animal model systems. Timed-pregnant rats were exposed to binge-like alcohol during either the first 10 days (first trimester equivalent) or second 10 days of gestation (second trimester equivalent), or the combination of first and second trimesters equivalent for prenatal treatments. Offspring from some of the animals exposed to alcohol during the combined first and second trimesters equivalent were raised artificially from postnatal day (P) 4 through P9 (part of the third trimester equivalent), and also received binge-like alcohol during this period, producing animals that were exposed to alcohol during all three trimesters equivalent. Offspring from untreated dams were also raised artificially and received alcohol only from P4 to P9, thus creating animals that were exposed to alcohol only during part of the third trimester equivalent. All pups were perfused on P10. Appropriate controls (nutritional and normally reared) were used for every alcohol treatment combination. Peak blood alcohol concentrations were not different among the treatment groups for a given sampling time. Significant somatic growth deficits occurred in offspring exposed to alcohol for the equivalent of all three trimesters, compared with offspring exposed to alcohol during other periods. Brain growth in offspring also was significantly affected by the timing of alcohol exposure. The whole brain, forebrain, and cerebellum to body weight ratios of pups exposed to alcohol during the third trimester had more significant brain growth deficits than pups in groups exposed to alcohol during other times of brain development. Although alcohol exposure during the third trimester had a significant detrimental impact on overall brain growth, significant differences in temporal vulnerability were also found for the brainstem to body weight ratios. Offspring of dams exposed to alcohol during the first trimester had the same magnitude of deficit as those exposed to alcohol during the third trimester, and those two groups were significantly deficient compared with the groups exposed to alcohol at other times, suggesting some differential vulnerability of this region to alcohol-induced injury at different times of development. This study is the first thorough examination of microencephaly and gross regional vulnerability of the developing brain as related to temporal factors of alcohol exposure in an animal model system, and the results support and expand on the findings of the available clinical literature. Furthermore, our results substantiate claims that the cessation of alcohol before the third trimester can lessen the severity of some alcohol-related birth deficits.

Alcoholic Intoxication↗

Reactivity to alcohol cues in alcoholics and non-alcoholics: implications for a stimulus control analysis of drinking.

The present study is an attempt to identify responses to alcohol-related stimuli which might differentiate alcoholics from non-alcoholics. The assumption was that alcoholics would be more reactive to alcohol cues because of prior conditioning history with respect to alcohol and drinking. Eight alcoholics in treatment were compared with ten non-alcoholic controls and two recovering alcoholics, using swallowing and salivation as the principal dependent measures. (The concordance of swallowing and salivation was validated using dental rolls with an independent group of ten alcoholics.) Five-minute "sniff-trials" were provided in which subjects smelled either cedar chips or their favorite alcoholic beverage, in a labelled container. Swallowing (salivation) and craving (desire to drink alcohol) were significantly elevated in alcohol-sniffing trials for alcoholics in treatment compared with non-alcoholics; cardiac rate and galvanic skin response duration were also elevated in alcoholics in treatment, though not significantly. Recovering alcoholics resembled alcoholics in treatment more closely than they resembled non-alcoholics. The data were examined in the context of conditioned withdrawal resembled non-alcoholics. The data were examined in the context of conditioned withdrawal and homeostatic protective mechanisms. Implications for the stimulus control analysis of drinking were discussed.

Adult↗

Alcohol outcome expectancies and risk for alcohol use problems in women with and without a family history of alcoholism.

Studies have shown that alcohol expectancies are positively associated with drinking and alcohol abuse and dependence symptoms among alcohol users. This study looked at the relationship of alcohol expectancies, family history of alcoholism, menstrual cycle and drinking behavior. The present study compared alcohol expectancies using the Alcohol Expectancy Questionnaire (AEQ) in 85 women ranging from 18 to 35 years of age. Forty-one women had a confirmed parental history of alcoholism (family history positive, FHP) and 44 women had no parental history of alcoholism (family history negative, FHN). Participants' mood, alcohol consumption, and daily consequences of alcohol use were prospectively tracked across one menstrual cycle. Alcohol expectancies at screening were significantly greater in FHP women in four of the six AEQ subscales, as well as the composite score. Alcohol expectancies correlated significantly with drinking behavior among FHN women. In FHP women, alcohol expectancies were elevated regardless of their drinking level. Alcohol expectancies decreased among FHP women, but not FHN women, after prospectively tracking their drinking behavior and consequences of drinking. Negative outcomes of drinking were increased among the FHP women who were heavy drinkers. Irrespective of family history status, alcohol use in moderate drinkers increased significantly during menses compared to the follicular and luteal phases of the menstrual cycle. These findings suggest that menstrual cycle may also play a role in alcohol consumption. Thus, the results of the present study indicate that issues related to the level of alcohol consumption, menstrual cycle phase and family history of alcoholism should be considered when addressing alcohol abuse in women.

Adolescent↗

Alcohol use by alcoholics with and without a history of parental alcoholism.

The association between parental history of alcoholism and the nature of alcoholism was assessed using a more reliable measure of family history (Family Tree Questionnaire) and a more comprehensive inventory of alcoholism (Alcohol Use Inventory) than used in earlier studies. Parental alcoholism was associated with more severe alcoholism on most parameters of alcohol use (age of onset, quantity, frequency, preoccupation, and sustained use) and alcohol-related problems (social, vocational, physical, cognitive, and loss of control). The association between parental history of alcoholism and more severe alcoholism in the probands was independent of age of onset of alcoholism, current age, socioeconomic background, and marital status. Parental history positive (PH+) alcoholics were more reliant on alcohol to manage their moods but did not differ significantly from parental history negative (PH-) alcoholics in the use of alcohol to improve sociability or mental functioning or to cope with marital problems. Surprisingly, the degree of concern, guilt, and worry over the negative consequences of drinking was not significantly different for PH+ alcoholics although the negative consequences were clearly much more severe for this group. While the data are inconclusive about the reasons for more severe alcoholism in PH+ alcoholics, greater reliance on ethanol to manage moods and a relative insensitivity to negative consequences could theoretically account for the vulnerability to more severe alcoholism found in PH+ alcoholics.

Adaptation, Psychological↗

Suppressing effect of the cannabinoid CB1 receptor antagonist, SR147778, on alcohol intake and motivational properties of alcohol in alcohol-preferring sP rats.

AIMS: The present study investigated the effect of the newly synthesized cannabinoid CB(1) receptor antagonist, SR147778, on alcohol intake and the motivational properties of alcohol in selectively bred Sardinian alcohol-preferring (sP) rats. METHODS AND RESULTS: In Experiment 1, the repeated administration of SR147778 (0.3-3 mg/kg twice daily, i.p.) specifically suppressed the acquisition of alcohol drinking behaviour in alcohol-naive rats exposed to the two-bottle "alcohol vs water" choice regimen for 24 h/day. In Experiment 2, an acute administration of SR147778 (2.5-10 mg/kg, i.p.) specifically reduced alcohol intake in alcohol-experienced rats that were given alcohol and water under the two-bottle choice regimen in daily sessions of 4 h. In Experiment 3, an acute administration of SR147778 (0.3-3 mg/kg, i.p.) suppressed the "alcohol deprivation effect", i.e. the extra-intake of alcohol occurring after a period of alcohol abstinence. In Experiment 4, an acute administration of SR147778 (0.3-3 mg/kg, i.p.) specifically suppressed the extinction responding for alcohol, i.e. the maximal number of lever responses reached in the absence of alcohol in rats trained to lever-press for alcohol (measure of the motivational properties of alcohol). In Experiment 5, the combination of 3 mg/kg of SR147778 (i.p.) and 0.5 g/kg of alcohol (i.p.), a dose comparable with those usually consumed by sP rats in each drinking binge, failed to induce any conditioned taste aversion. CONCLUSION: Taken together, these results extend to SR147778 the anti-alcohol profile of the prototype cannabinoid CB(1) receptor antagonist, rimonabant (SR141716), and strengthen the hypothesis that the cannabinoid CB(1) receptor is part of the neural substrate mediating alcohol intake and the motivational properties of alcohol.

Alcohol Drinking↗